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Dynamics and Timekeeping in Biological Systems Christopher M. Dobson Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; email: [email protected]
Annu. Rev. Biochem. 2014. 83:159–64
Keywords
First published online as a Review in Advance on March 3, 2014
circadian rhythms, molecular clocks, entrainment, chronobiology, molecular dynamics
The Annual Review of Biochemistry is online at biochem.annualreviews.org This article’s doi: 10.1146/annurev-biochem-013014-102724
Abstract This article introduces three reviews on the theme of circadian rhythms.
c 2014 by Annual Reviews. Copyright All rights reserved
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Contents INTRODUCTION . . . . . . . . . . . . . . . . . . TIME-DEPENDENT BIOLOGICAL PROCESSES . . . . . . . . . . . . . . . . . . . . . . Diurnal Rhythms . . . . . . . . . . . . . . . . . . Oscillatory Phenomena . . . . . . . . . . . . Circadian Clocks . . . . . . . . . . . . . . . . . . . LOOKING INTO THE FUTURE . . .
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INTRODUCTION Biology is inherently a dynamic phenomenon, and the nature and timescales of molecular fluctuations and the kinetics and mechanisms of chemical reactions are of fundamental importance in defining the characteristics of all living systems. One aspect of biological dynamics that is particularly fascinating is the existence of a wide variety of oscillatory time-dependent phenomena ranging from the regular beating of our hearts to the familiar responses of many living systems to the changing seasons of the year. Among the most remarkable examples of such phenomena, however, are the circadian rhythms that link many fundamental processes of life to the rotation of the Earth about its axis. The next three articles in this volume (1–3) are devoted to descriptions of the dramatic progress that is being made in understanding the mechanisms of the molecular clocks that determine such rhythms and the way in which they are coupled to their internal and external environments.
TIME-DEPENDENT BIOLOGICAL PROCESSES Much of biology is dominated by the rates of chemical and physical processes rather than by the intrinsic stability of the multitude of components that are involved. Living systems are inherently out of equilibrium with their surroundings, utilizing energy from external sources, ultimately the Sun, to maintain their viability. As a result, both kinetic and thermo160
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dynamic factors are involved in virtually all of the events on which the existence and regulation of life depend. It is well established that the rates, and hence the products, of chemical reactions are controlled by enzymes, and it is becoming increasingly clear that other processes, such as the maintenance of metastable proteins in their functional states, are subject to equally stringent management (4). Failure of such regulation can lead to a loss of homeostasis and result in a variety of pathological conditions. For example, metabolic disorders can result from perturbations of enzymatic reactions; cancers may arise from disruptions in transcriptional processes and the cell cycle; and neurodegenerative disorders, such as Alzheimer’s disease, are commonly linked to protein misfolding and aggregation. The existence of temporal rhythms, associated with, for example, the circulation of the blood, patterns of sleeping and waking, and responses to the changing seasons, is a particularly fascinating aspect of biological dynamics. The existence of intrinsic dynamic as well as static properties of biological systems is well established, and the inherent fluctuations within macromolecular structures such as proteins have been explored in particular detail and linked with processes ranging from their ability to fold to functional structures to the mechanism of enzyme action (5). Many of these intrinsic fluctuations are extremely fast, often taking place on picosecond to millisecond timescales, whereas the timescales of oscillatory processes can occur over dramatically longer timescales, from seconds to months and years, suggesting that these slower periodic motions are likely to be dependent on more complex processes, such as the time-dependent interactions of multiple macromolecular components. Moreover, it is clear that many of these rhythmic processes are strongly coupled in some way to external conditions, such as temperature and light, and to a wide variety of physiological processes taking place within the organisms concerned (1–3). The general area of study of periodic biological phenomena is known as chronobiology and is a topic of fundamental and increasing
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interest in a multitude of disciplines across the physical, biological, and medical sciences. Few aspects of this topic are more fascinating than those that are linked to the daily cycle of the rising and setting of the Sun. This phenomenon has fascinated humans throughout all of history, and many ideas have been put forward as to its mechanism. The ancient Egyptians attributed the daily round to the journey of the god Ra, who traveled through the sky each day and through the underworld each night, before emerging to repeat the endless cycle. The recognition that the Earth rotated every 24 h about the axis joining its two poles, causing periodic changes in the exposure of individual places on the Earth’s surface to the Sun’s rays, has provided since the sixteenth century an explanation of night and day that is firmly based on science rather than speculation or mythology. But from very early times it was also recognized that living systems had some form of inbuilt sense of time that is inherent in their makeup, although linked to external stimuli such as light and temperature.
Diurnal Rhythms The recognition of periodic events in living systems taking place on a daily basis goes back more than two millennia, with observations such as the opening and closing of the leaves of certain plants and trees between day and night. Then, in the eighteenth century it was recognized that some such movements were not simply dependent on the effects of light, because they were observed to continue when the plants concerned were kept in the dark. The recognition that animals can maintain a roughly 24-h cycle in the absence of external stimuli became clear at the beginning on the nineteenth century, and a series of famous experiments involving humans remaining in the dark for prolonged periods gave clear evidence for an inherent “clock” within our own bodies. A particularly interesting fact that emerged from such experiments is that the endogenous cycles in the absence of stimuli are only approximately 24 h, an observation that gave rise in the twentieth
century to the term circadian (from the Latin circa, “about,” and dies, “day”). In diurnal animals the period is observed to be slightly longer than 24 h, whereas in nocturnal animals it is generally found to be slightly shorter than 24 h. These observations reveal that circadian rhythms experience entrainment, the process by which external fluctuations, such as the daily light–dark cycle, can result in the perturbation of the endogenous clocks so that they match the frequency of the fluctuations, in this particular case causing the period to become exactly that of the rotation of the Earth. It is also evident that entrainment allows circadian clocks to be reset by external stimuli, an event that is all too familiar to anyone traveling rapidly across time zones through the experience of jet lag, a phenomenon that demonstrates that a range of physiological processes are influenced by circadian clocks and that the resetting process can take some time. Circadian rhythms have also been found to exhibit other important characteristics, such as the phenomenon of temperature compensation, through which periodicity can be maintained as the temperature is varied, as many organisms experience very different physiological temperatures but largely retain their oscillatory periods in the region of 24 h. Circadian rhythms have now been identified in organisms ranging from bacteria to humans (1–3). Indeed, it is possible that they originated in the earliest types of cells, perhaps for specific chemical purposes such as protecting sensitive nucleic acids from UV radiation. Also, of course, differences in behavior during day and night are common in many present-day creatures, enhancing their ability to thrive in their particular environments. A major question arises, therefore, as to the molecular basis of circadian rhythms and the manner in which periodic behavior can be generated within such a wide range of cells and organisms.
Oscillatory Phenomena The idea of a clock that utilizes physicochemical principles is in itself a very familiar one. The motion of a pendulum has been known for www.annualreviews.org • Dynamics and Timekeeping in Biology
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centuries, although it was only during the seventeenth century that an understanding of the nature of its periodic behavior led to its use in clocks, and thereby enabled people to begin to keep track of time with very much greater accuracy than had previously been possible. In the nineteenth century, “chemical clocks” were discovered and are still quite fascinating as they can make colorful demonstrations of the wonders of science. Chemical clocks (6) are typically based on oscillatory chemical reactions in which the concentration of one or more components of a reaction mixture exhibits periodic changes. These chemical systems are inherently significant because they show that the course of a reaction does not have to be dominated by behavior predicted from simple equilibrium thermodynamics, although without the input of energy, such as occurs in biological systems, the amplitudes of the periodic changes steadily decrease. Oscillatory chemical behavior can arise in certain reactions that can follow more than one pathway, if one of these pathways generates an intermediate that is consumed in another. When the concentration of the intermediate is low, the pathway through which it is produced will dominate, but when the concentration of the intermediate becomes high enough, a switch will occur so that the pathway that consumes the intermediate becomes dominant, resulting in periodic oscillations in the concentrations of the reacting species. It is perhaps interesting in the context of this article that inclusion of an appropriate photon-absorbing catalyst can sometimes enable such oscillatory chemical reactions to be modulated by light. The idea of very well defined oscillatory motions in biology is also very familiar; perhaps the most highly studied example is the cardiac cycle that involves a number of distinct stages in which the atria contract to force blood through the ventricles into the pulmonary artery and the aorta. Unlike the motions of skeletal muscle, the contractions of cardiac muscle are generated by the muscle cells themselves and do not require stimulus through the nervous system, as cardiac “pacemaker cells” undergo spontaneous depolarization to generate rhythmic ac-
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tion potentials that trigger the regular contractions of cardiac muscle. It has been known for many years that action potentials result from time-dependent changes in the concentrations of sodium and potassium ions as a result of the opening and closing of specific ion channels located within cell membranes. Recently, however, the mechanisms by which such channels function has become much clearer at the molecular level, particularly through the determination of a number of their structures at atomic resolution (7). In an interesting parallel to the circadian cycle, the normal functional heart rate is slower than the intrinsic depolarization frequency, as it too is modulated by coupling to external factors, for example, those resulting from exercise or through hormonal stimulation.
Circadian Clocks Anatomical studies have led to the identification of structures within the hypothalamus of the brain that are associated with oscillatory behavior that can be entrained by signals resulting from the eye and, in fact, from a range of peripheral organs. It is becoming increasingly evident, however, that circadian oscillators exist in a wide range of tissues and that they can be coupled in a variety of ways to the “central pacemaker” located in the hypothalamus. In recent years, our knowledge and understanding of the specific molecular mechanisms that underlie circadian rhythms have advanced very rapidly (1–3). Important clues emerged in the 1970s through the study of mutant fruit flies and resulted in the mapping of the first genetic component of a circadian clock, appropriately named the period gene. By the 1990s, mammalian clock genes had been identified, and since then an increasing number of genes has been identified in a wide variety of different organisms, paving the way for investigations of the fundamental molecular mechanisms behind these fascinating phenomena. It rapidly became clear that regulation of transcription and translation was likely to be strongly associated with the timekeeping process. Interestingly in this regard, a fundamental principle of such a
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mechanism involves a transcriptional activator that induces the transcription of a repressor that accumulates over time until it reaches a sufficient level to repress its own activation, generating a feedback loop. Such a mechanism has features that have interesting parallels to those discussed above in the context of the oscillatory behavior of chemical clocks. It is becoming increasingly evident, however, that other types of mechanisms can exist that are associated with a range of metabolic processes. The most striking evidence for this assertion is the discovery within the past decade that a molecular clock from cyanobacteria, involving a series of phosphorylation reactions, can be reconstituted in the laboratory from just three proteins with ATP as an energy source (8); this observation has been followed by an increasing number of studies that show that nontranscriptional circadian clocks are likely to be present in the cells of a very wide range of other organisms, including humans. The three reviews that follow discuss in detail key aspects of our present understanding of the molecular origins of circadian clocks from complementary perspectives. Reddy & Rey (1) outline our current knowledge of transcriptionbased mechanisms of circadian timekeeping, noting the existence of the type of feedback loop mentioned briefly above, and then discuss increasing evidence for the possible nature and functional importance of metabolic and nontranscriptional processes in the periodic behavior of eukaryotic systems. They discuss further the fact that a number of processes occurring in the cytosol generate feedback to transcriptional oscillators, forming accessory feedback loops linking cellular clocks to cellular metabolism. Their conclusion is that living systems are likely to have evolved multiple coupled oscillators to fulfill all the requirements of an effective clock, and they raise the fascinating issue of a possible distinction between mechanisms that keep time and those that tell time within living systems. In their review, Crane & Young (2) also focus on eukaryotic systems, and explore in particular the ways in which posttranslational
factors can be essential to the production of molecular oscillators. They discuss in detail the ways in which posttranslational modifications, such as protein phosphorylation, can affect the structures and functions of the transcriptional activators and repressors of a circadian clock. In this context they draw attention to the fact that high-resolution structures of increasing numbers of clock proteins are being reported, and that information about the nature and time dependence of the interactions between these proteins is beginning to emerge. The results of such investigations are already beginning to provide key information about the molecular events associated with specific metabolic and developmental pathways. Overall, these authors conclude that “conserved motifs and structural frameworks have been elaborated into a highly dynamic collection of interacting molecules that undergo orchestrated changes in chemical structure, conformational state, and partners” (2, p. 191). Johnson & Egli (3) focus on the key issue that molecular clocks in biology are not only accurate but also robust, as indicated by their ability to resist a variety of environmental and metabolic fluctuations. Particularly notable in this regard is insensitivity to temperature, as molecular fluctuations and chemical reactions generally exhibit high dependences on this parameter as a consequence of the increasing ease of crossing energetic barriers as the temperature is raised. These authors focus on the circadian systems of cyanobacteria, for which the structures of many key molecular components have been determined, to discuss how the coupling of transcriptional and nontranscriptional oscillators can promote resilience, and they conclude that temperature compensation is in fact a subset of a much larger phenomenon of metabolic compensation, which maintains the frequency of the oscillators in response to a large number of potentially disruptive factors.
LOOKING INTO THE FUTURE The rapidly developing field of chronobiology illustrates particularly clearly the tremendous www.annualreviews.org • Dynamics and Timekeeping in Biology
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significance for living systems of the dynamical behavior of macromolecules and macromolecular complexes, and the way that the motions involved can be coupled in exquisite ways to complex physiological processes. It is clear, however, that despite the dramatic progress of recent years, much remains to be learned about the detailed mechanism of circadian rhythms, not least concerning the relative importance of transcriptional and metabolic processes and the manner in which they interact with each other. Much progress is likely to be made in the future through continuing developments in genomic analysis, from the further utilization of the techniques of molecular and structural biology
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to define the conformations of key proteins and the interactions between them, and through our increasing understanding of the structural and dynamical behavior within and between cells. The three reviews in this volume on the topic of circadian clocks also touch on the practical advances that could arise from an increased knowledge of this field of science, including the possibility of manipulating gene activity and metabolic pathways to improve the expression of valuable bioproducts (3) and the opportunity to gain a greater understanding of the link between disruption of circadian rhythms and a wide variety of human diseases ranging from cancer to neuronal disorders (1).
DISCLOSURE STATEMENT The author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review. LITERATURE CITED 1. Reddy AB, Rey G. 2014. Metabolic and nontranscriptional circadian clocks: eukaryotes. Annu. Rev. Biochem. 83:165–89 2. Crane BR, Young MW. 2014. Interactive features of proteins composing eukaryotic circadian clocks. Annu. Rev. Biochem. 83:191–219 3. Johnson CH, Egli M. 2014. Metabolic compensation and circadian resilience in prokaryotic cyanobacteria. Annu. Rev. Biochem. 83:221–47 4. Dobson CM. 2003. Protein folding and misfolding. Nature 426:884–90 5. Karplus M, McCammon AJ. 2002. Molecular dynamics simulations of biomolecules. Nat. Struct. Biol. 9:646–52 6. Noyes RM, Field RJ. 1974. Oscillatory chemical reactions. Annu. Rev. Phys. Chem. 25:95–119 7. Gouaux E, Mackinnon R. 2005. Principles of selective ion transport in channels and pumps. Science 310:1461–65 8. Nakajima M, Imai K, Ito H, Nishiwaki T, Murayama Y, et al. 2005. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308:414–15
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Contents
Annual Review of Biochemistry Volume 83, 2014
Annu. Rev. Biochem. 2014.83:159-164. Downloaded from www.annualreviews.org by Oregon State University on 06/15/14. For personal use only.
Journeys in Science: Glycobiology and Other Paths Raymond A. Dwek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Lipids and Extracellular Materials William Dowhan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45 Topological Regulation of Lipid Balance in Cells Guillaume Drin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p51 Lipidomics: Analysis of the Lipid Composition of Cells and Subcellular Organelles by Electrospray Ionization Mass Spectrometry Britta Brugger ¨ p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p79 Biosynthesis and Export of Bacterial Lipopolysaccharides Chris Whitfield and M. Stephen Trent p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p99 Demystifying Heparan Sulfate–Protein Interactions Ding Xu and Jeffrey D. Esko p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 129 Dynamics and Timekeeping in Biological Systems Christopher M. Dobson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 159 Metabolic and Nontranscriptional Circadian Clocks: Eukaryotes Akhilesh B. Reddy and Guillaume Rey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 165 Interactive Features of Proteins Composing Eukaryotic Circadian Clocks Brian R. Crane and Michael W. Young p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 191 Metabolic Compensation and Circadian Resilience in Prokaryotic Cyanobacteria Carl Hirschie Johnson and Martin Egli p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 221 Activity-Based Profiling of Proteases Laura E. Sanman and Matthew Bogyo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249 Asymmetry of Single Cells and Where That Leads Mark S. Bretscher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 275 Bringing Dynamic Molecular Machines into Focus by Methyl-TROSY NMR Rina Rosenzweig and Lewis E. Kay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291
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Chlorophyll Modifications and Their Spectral Extension in Oxygenic Photosynthesis Min Chen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317 Enzyme Inhibitor Discovery by Activity-Based Protein Profiling Micah J. Niphakis and Benjamin F. Cravatt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 341 Expanding and Reprogramming the Genetic Code of Cells and Animals Jason W. Chin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 379 Genome Engineering with Targetable Nucleases Dana Carroll p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 409 Annu. Rev. Biochem. 2014.83:159-164. Downloaded from www.annualreviews.org by Oregon State University on 06/15/14. For personal use only.
Hierarchy of RNA Functional Dynamics Anthony M. Mustoe, Charles L. Brooks, and Hashim M. Al-Hashimi p p p p p p p p p p p p p p p p p p 441 High-Resolution Structure of the Eukaryotic 80S Ribosome Gulnara Yusupova and Marat Yusupov p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 467 Histone Chaperones: Assisting Histone Traffic and Nucleosome Dynamics Zachary A. Gurard-Levin, Jean-Pierre Quivy, and Genevi`eve Almouzni p p p p p p p p p p p p p p 487 Human RecQ Helicases in DNA Repair, Recombination, and Replication Deborah L. Croteau, Venkateswarlu Popuri, Patricia L. Opresko, and Vilhelm A. Bohr p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519 Intrinsically Disordered Proteins and Intrinsically Disordered Protein Regions Christopher J. Oldfield and A. Keith Dunker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 553 Mechanism and Function of Oxidative Reversal of DNA and RNA Methylation Li Shen, Chun-Xiao Song, Chuan He, and Yi Zhang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 585 Progress Toward Synthetic Cells J. Craig Blain and Jack W. Szostak p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 615 PTEN Carolyn A. Worby and Jack E. Dixon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 641 Regulating the Chromatin Landscape: Structural and Mechanistic Perspectives Blaine Bartholomew p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 671 RNA Helicase Proteins as Chaperones and Remodelers Inga Jarmoskaite and Rick Russell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 697
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Selection-Based Discovery of Druglike Macrocyclic Peptides Toby Passioura, Takayuki Katoh, Yuki Goto, and Hiroaki Suga p p p p p p p p p p p p p p p p p p p p p p p p p 727 Small Proteins Can No Longer Be Ignored Gisela Storz, Yuri I. Wolf, and Kumaran S. Ramamurthi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 753 The Scanning Mechanism of Eukaryotic Translation Initiation Alan G. Hinnebusch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 779 Understanding Nucleic Acid–Ion Interactions Jan Lipfert, Sebastian Doniach, Rhiju Das, and Daniel Herschlag p p p p p p p p p p p p p p p p p p p p p p 813
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Indexes Cumulative Index of Contributing Authors, Volumes 79–83 p p p p p p p p p p p p p p p p p p p p p p p p p p p 843 Cumulative Index of Article Titles, Volumes 79–83 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 847 Errata An online log of corrections to Annual Review of Biochemistry articles may be found at http://www.annualreviews.org/errata/biochem
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Dynamics and Timekeeping in Biological Systems Christopher M. Dobson Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; email: [email protected]
Annu. Rev. Biochem. 2014. 83:159–64
Keywords
First published online as a Review in Advance on March 3, 2014
circadian rhythms, molecular clocks, entrainment, chronobiology, molecular dynamics
The Annual Review of Biochemistry is online at biochem.annualreviews.org This article’s doi: 10.1146/annurev-biochem-013014-102724
Abstract This article introduces three reviews on the theme of circadian rhythms.
c 2014 by Annual Reviews. Copyright All rights reserved
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Contents INTRODUCTION . . . . . . . . . . . . . . . . . . TIME-DEPENDENT BIOLOGICAL PROCESSES . . . . . . . . . . . . . . . . . . . . . . Diurnal Rhythms . . . . . . . . . . . . . . . . . . Oscillatory Phenomena . . . . . . . . . . . . Circadian Clocks . . . . . . . . . . . . . . . . . . . LOOKING INTO THE FUTURE . . .
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INTRODUCTION Biology is inherently a dynamic phenomenon, and the nature and timescales of molecular fluctuations and the kinetics and mechanisms of chemical reactions are of fundamental importance in defining the characteristics of all living systems. One aspect of biological dynamics that is particularly fascinating is the existence of a wide variety of oscillatory time-dependent phenomena ranging from the regular beating of our hearts to the familiar responses of many living systems to the changing seasons of the year. Among the most remarkable examples of such phenomena, however, are the circadian rhythms that link many fundamental processes of life to the rotation of the Earth about its axis. The next three articles in this volume (1–3) are devoted to descriptions of the dramatic progress that is being made in understanding the mechanisms of the molecular clocks that determine such rhythms and the way in which they are coupled to their internal and external environments.
TIME-DEPENDENT BIOLOGICAL PROCESSES Much of biology is dominated by the rates of chemical and physical processes rather than by the intrinsic stability of the multitude of components that are involved. Living systems are inherently out of equilibrium with their surroundings, utilizing energy from external sources, ultimately the Sun, to maintain their viability. As a result, both kinetic and thermo160
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dynamic factors are involved in virtually all of the events on which the existence and regulation of life depend. It is well established that the rates, and hence the products, of chemical reactions are controlled by enzymes, and it is becoming increasingly clear that other processes, such as the maintenance of metastable proteins in their functional states, are subject to equally stringent management (4). Failure of such regulation can lead to a loss of homeostasis and result in a variety of pathological conditions. For example, metabolic disorders can result from perturbations of enzymatic reactions; cancers may arise from disruptions in transcriptional processes and the cell cycle; and neurodegenerative disorders, such as Alzheimer’s disease, are commonly linked to protein misfolding and aggregation. The existence of temporal rhythms, associated with, for example, the circulation of the blood, patterns of sleeping and waking, and responses to the changing seasons, is a particularly fascinating aspect of biological dynamics. The existence of intrinsic dynamic as well as static properties of biological systems is well established, and the inherent fluctuations within macromolecular structures such as proteins have been explored in particular detail and linked with processes ranging from their ability to fold to functional structures to the mechanism of enzyme action (5). Many of these intrinsic fluctuations are extremely fast, often taking place on picosecond to millisecond timescales, whereas the timescales of oscillatory processes can occur over dramatically longer timescales, from seconds to months and years, suggesting that these slower periodic motions are likely to be dependent on more complex processes, such as the time-dependent interactions of multiple macromolecular components. Moreover, it is clear that many of these rhythmic processes are strongly coupled in some way to external conditions, such as temperature and light, and to a wide variety of physiological processes taking place within the organisms concerned (1–3). The general area of study of periodic biological phenomena is known as chronobiology and is a topic of fundamental and increasing
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interest in a multitude of disciplines across the physical, biological, and medical sciences. Few aspects of this topic are more fascinating than those that are linked to the daily cycle of the rising and setting of the Sun. This phenomenon has fascinated humans throughout all of history, and many ideas have been put forward as to its mechanism. The ancient Egyptians attributed the daily round to the journey of the god Ra, who traveled through the sky each day and through the underworld each night, before emerging to repeat the endless cycle. The recognition that the Earth rotated every 24 h about the axis joining its two poles, causing periodic changes in the exposure of individual places on the Earth’s surface to the Sun’s rays, has provided since the sixteenth century an explanation of night and day that is firmly based on science rather than speculation or mythology. But from very early times it was also recognized that living systems had some form of inbuilt sense of time that is inherent in their makeup, although linked to external stimuli such as light and temperature.
Diurnal Rhythms The recognition of periodic events in living systems taking place on a daily basis goes back more than two millennia, with observations such as the opening and closing of the leaves of certain plants and trees between day and night. Then, in the eighteenth century it was recognized that some such movements were not simply dependent on the effects of light, because they were observed to continue when the plants concerned were kept in the dark. The recognition that animals can maintain a roughly 24-h cycle in the absence of external stimuli became clear at the beginning on the nineteenth century, and a series of famous experiments involving humans remaining in the dark for prolonged periods gave clear evidence for an inherent “clock” within our own bodies. A particularly interesting fact that emerged from such experiments is that the endogenous cycles in the absence of stimuli are only approximately 24 h, an observation that gave rise in the twentieth
century to the term circadian (from the Latin circa, “about,” and dies, “day”). In diurnal animals the period is observed to be slightly longer than 24 h, whereas in nocturnal animals it is generally found to be slightly shorter than 24 h. These observations reveal that circadian rhythms experience entrainment, the process by which external fluctuations, such as the daily light–dark cycle, can result in the perturbation of the endogenous clocks so that they match the frequency of the fluctuations, in this particular case causing the period to become exactly that of the rotation of the Earth. It is also evident that entrainment allows circadian clocks to be reset by external stimuli, an event that is all too familiar to anyone traveling rapidly across time zones through the experience of jet lag, a phenomenon that demonstrates that a range of physiological processes are influenced by circadian clocks and that the resetting process can take some time. Circadian rhythms have also been found to exhibit other important characteristics, such as the phenomenon of temperature compensation, through which periodicity can be maintained as the temperature is varied, as many organisms experience very different physiological temperatures but largely retain their oscillatory periods in the region of 24 h. Circadian rhythms have now been identified in organisms ranging from bacteria to humans (1–3). Indeed, it is possible that they originated in the earliest types of cells, perhaps for specific chemical purposes such as protecting sensitive nucleic acids from UV radiation. Also, of course, differences in behavior during day and night are common in many present-day creatures, enhancing their ability to thrive in their particular environments. A major question arises, therefore, as to the molecular basis of circadian rhythms and the manner in which periodic behavior can be generated within such a wide range of cells and organisms.
Oscillatory Phenomena The idea of a clock that utilizes physicochemical principles is in itself a very familiar one. The motion of a pendulum has been known for www.annualreviews.org • Dynamics and Timekeeping in Biology
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centuries, although it was only during the seventeenth century that an understanding of the nature of its periodic behavior led to its use in clocks, and thereby enabled people to begin to keep track of time with very much greater accuracy than had previously been possible. In the nineteenth century, “chemical clocks” were discovered and are still quite fascinating as they can make colorful demonstrations of the wonders of science. Chemical clocks (6) are typically based on oscillatory chemical reactions in which the concentration of one or more components of a reaction mixture exhibits periodic changes. These chemical systems are inherently significant because they show that the course of a reaction does not have to be dominated by behavior predicted from simple equilibrium thermodynamics, although without the input of energy, such as occurs in biological systems, the amplitudes of the periodic changes steadily decrease. Oscillatory chemical behavior can arise in certain reactions that can follow more than one pathway, if one of these pathways generates an intermediate that is consumed in another. When the concentration of the intermediate is low, the pathway through which it is produced will dominate, but when the concentration of the intermediate becomes high enough, a switch will occur so that the pathway that consumes the intermediate becomes dominant, resulting in periodic oscillations in the concentrations of the reacting species. It is perhaps interesting in the context of this article that inclusion of an appropriate photon-absorbing catalyst can sometimes enable such oscillatory chemical reactions to be modulated by light. The idea of very well defined oscillatory motions in biology is also very familiar; perhaps the most highly studied example is the cardiac cycle that involves a number of distinct stages in which the atria contract to force blood through the ventricles into the pulmonary artery and the aorta. Unlike the motions of skeletal muscle, the contractions of cardiac muscle are generated by the muscle cells themselves and do not require stimulus through the nervous system, as cardiac “pacemaker cells” undergo spontaneous depolarization to generate rhythmic ac-
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tion potentials that trigger the regular contractions of cardiac muscle. It has been known for many years that action potentials result from time-dependent changes in the concentrations of sodium and potassium ions as a result of the opening and closing of specific ion channels located within cell membranes. Recently, however, the mechanisms by which such channels function has become much clearer at the molecular level, particularly through the determination of a number of their structures at atomic resolution (7). In an interesting parallel to the circadian cycle, the normal functional heart rate is slower than the intrinsic depolarization frequency, as it too is modulated by coupling to external factors, for example, those resulting from exercise or through hormonal stimulation.
Circadian Clocks Anatomical studies have led to the identification of structures within the hypothalamus of the brain that are associated with oscillatory behavior that can be entrained by signals resulting from the eye and, in fact, from a range of peripheral organs. It is becoming increasingly evident, however, that circadian oscillators exist in a wide range of tissues and that they can be coupled in a variety of ways to the “central pacemaker” located in the hypothalamus. In recent years, our knowledge and understanding of the specific molecular mechanisms that underlie circadian rhythms have advanced very rapidly (1–3). Important clues emerged in the 1970s through the study of mutant fruit flies and resulted in the mapping of the first genetic component of a circadian clock, appropriately named the period gene. By the 1990s, mammalian clock genes had been identified, and since then an increasing number of genes has been identified in a wide variety of different organisms, paving the way for investigations of the fundamental molecular mechanisms behind these fascinating phenomena. It rapidly became clear that regulation of transcription and translation was likely to be strongly associated with the timekeeping process. Interestingly in this regard, a fundamental principle of such a
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mechanism involves a transcriptional activator that induces the transcription of a repressor that accumulates over time until it reaches a sufficient level to repress its own activation, generating a feedback loop. Such a mechanism has features that have interesting parallels to those discussed above in the context of the oscillatory behavior of chemical clocks. It is becoming increasingly evident, however, that other types of mechanisms can exist that are associated with a range of metabolic processes. The most striking evidence for this assertion is the discovery within the past decade that a molecular clock from cyanobacteria, involving a series of phosphorylation reactions, can be reconstituted in the laboratory from just three proteins with ATP as an energy source (8); this observation has been followed by an increasing number of studies that show that nontranscriptional circadian clocks are likely to be present in the cells of a very wide range of other organisms, including humans. The three reviews that follow discuss in detail key aspects of our present understanding of the molecular origins of circadian clocks from complementary perspectives. Reddy & Rey (1) outline our current knowledge of transcriptionbased mechanisms of circadian timekeeping, noting the existence of the type of feedback loop mentioned briefly above, and then discuss increasing evidence for the possible nature and functional importance of metabolic and nontranscriptional processes in the periodic behavior of eukaryotic systems. They discuss further the fact that a number of processes occurring in the cytosol generate feedback to transcriptional oscillators, forming accessory feedback loops linking cellular clocks to cellular metabolism. Their conclusion is that living systems are likely to have evolved multiple coupled oscillators to fulfill all the requirements of an effective clock, and they raise the fascinating issue of a possible distinction between mechanisms that keep time and those that tell time within living systems. In their review, Crane & Young (2) also focus on eukaryotic systems, and explore in particular the ways in which posttranslational
factors can be essential to the production of molecular oscillators. They discuss in detail the ways in which posttranslational modifications, such as protein phosphorylation, can affect the structures and functions of the transcriptional activators and repressors of a circadian clock. In this context they draw attention to the fact that high-resolution structures of increasing numbers of clock proteins are being reported, and that information about the nature and time dependence of the interactions between these proteins is beginning to emerge. The results of such investigations are already beginning to provide key information about the molecular events associated with specific metabolic and developmental pathways. Overall, these authors conclude that “conserved motifs and structural frameworks have been elaborated into a highly dynamic collection of interacting molecules that undergo orchestrated changes in chemical structure, conformational state, and partners” (2, p. 191). Johnson & Egli (3) focus on the key issue that molecular clocks in biology are not only accurate but also robust, as indicated by their ability to resist a variety of environmental and metabolic fluctuations. Particularly notable in this regard is insensitivity to temperature, as molecular fluctuations and chemical reactions generally exhibit high dependences on this parameter as a consequence of the increasing ease of crossing energetic barriers as the temperature is raised. These authors focus on the circadian systems of cyanobacteria, for which the structures of many key molecular components have been determined, to discuss how the coupling of transcriptional and nontranscriptional oscillators can promote resilience, and they conclude that temperature compensation is in fact a subset of a much larger phenomenon of metabolic compensation, which maintains the frequency of the oscillators in response to a large number of potentially disruptive factors.
LOOKING INTO THE FUTURE The rapidly developing field of chronobiology illustrates particularly clearly the tremendous www.annualreviews.org • Dynamics and Timekeeping in Biology
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significance for living systems of the dynamical behavior of macromolecules and macromolecular complexes, and the way that the motions involved can be coupled in exquisite ways to complex physiological processes. It is clear, however, that despite the dramatic progress of recent years, much remains to be learned about the detailed mechanism of circadian rhythms, not least concerning the relative importance of transcriptional and metabolic processes and the manner in which they interact with each other. Much progress is likely to be made in the future through continuing developments in genomic analysis, from the further utilization of the techniques of molecular and structural biology
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to define the conformations of key proteins and the interactions between them, and through our increasing understanding of the structural and dynamical behavior within and between cells. The three reviews in this volume on the topic of circadian clocks also touch on the practical advances that could arise from an increased knowledge of this field of science, including the possibility of manipulating gene activity and metabolic pathways to improve the expression of valuable bioproducts (3) and the opportunity to gain a greater understanding of the link between disruption of circadian rhythms and a wide variety of human diseases ranging from cancer to neuronal disorders (1).
DISCLOSURE STATEMENT The author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review. LITERATURE CITED 1. Reddy AB, Rey G. 2014. Metabolic and nontranscriptional circadian clocks: eukaryotes. Annu. Rev. Biochem. 83:165–89 2. Crane BR, Young MW. 2014. Interactive features of proteins composing eukaryotic circadian clocks. Annu. Rev. Biochem. 83:191–219 3. Johnson CH, Egli M. 2014. Metabolic compensation and circadian resilience in prokaryotic cyanobacteria. Annu. Rev. Biochem. 83:221–47 4. Dobson CM. 2003. Protein folding and misfolding. Nature 426:884–90 5. Karplus M, McCammon AJ. 2002. Molecular dynamics simulations of biomolecules. Nat. Struct. Biol. 9:646–52 6. Noyes RM, Field RJ. 1974. Oscillatory chemical reactions. Annu. Rev. Phys. Chem. 25:95–119 7. Gouaux E, Mackinnon R. 2005. Principles of selective ion transport in channels and pumps. Science 310:1461–65 8. Nakajima M, Imai K, Ito H, Nishiwaki T, Murayama Y, et al. 2005. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308:414–15
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Contents
Annual Review of Biochemistry Volume 83, 2014
Annu. Rev. Biochem. 2014.83:159-164. Downloaded from www.annualreviews.org by Oregon State University on 06/15/14. For personal use only.
Journeys in Science: Glycobiology and Other Paths Raymond A. Dwek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Lipids and Extracellular Materials William Dowhan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45 Topological Regulation of Lipid Balance in Cells Guillaume Drin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p51 Lipidomics: Analysis of the Lipid Composition of Cells and Subcellular Organelles by Electrospray Ionization Mass Spectrometry Britta Brugger ¨ p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p79 Biosynthesis and Export of Bacterial Lipopolysaccharides Chris Whitfield and M. Stephen Trent p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p99 Demystifying Heparan Sulfate–Protein Interactions Ding Xu and Jeffrey D. Esko p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 129 Dynamics and Timekeeping in Biological Systems Christopher M. Dobson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 159 Metabolic and Nontranscriptional Circadian Clocks: Eukaryotes Akhilesh B. Reddy and Guillaume Rey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 165 Interactive Features of Proteins Composing Eukaryotic Circadian Clocks Brian R. Crane and Michael W. Young p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 191 Metabolic Compensation and Circadian Resilience in Prokaryotic Cyanobacteria Carl Hirschie Johnson and Martin Egli p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 221 Activity-Based Profiling of Proteases Laura E. Sanman and Matthew Bogyo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249 Asymmetry of Single Cells and Where That Leads Mark S. Bretscher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 275 Bringing Dynamic Molecular Machines into Focus by Methyl-TROSY NMR Rina Rosenzweig and Lewis E. Kay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291
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Chlorophyll Modifications and Their Spectral Extension in Oxygenic Photosynthesis Min Chen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317 Enzyme Inhibitor Discovery by Activity-Based Protein Profiling Micah J. Niphakis and Benjamin F. Cravatt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 341 Expanding and Reprogramming the Genetic Code of Cells and Animals Jason W. Chin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 379 Genome Engineering with Targetable Nucleases Dana Carroll p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 409 Annu. Rev. Biochem. 2014.83:159-164. Downloaded from www.annualreviews.org by Oregon State University on 06/15/14. For personal use only.
Hierarchy of RNA Functional Dynamics Anthony M. Mustoe, Charles L. Brooks, and Hashim M. Al-Hashimi p p p p p p p p p p p p p p p p p p 441 High-Resolution Structure of the Eukaryotic 80S Ribosome Gulnara Yusupova and Marat Yusupov p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 467 Histone Chaperones: Assisting Histone Traffic and Nucleosome Dynamics Zachary A. Gurard-Levin, Jean-Pierre Quivy, and Genevi`eve Almouzni p p p p p p p p p p p p p p 487 Human RecQ Helicases in DNA Repair, Recombination, and Replication Deborah L. Croteau, Venkateswarlu Popuri, Patricia L. Opresko, and Vilhelm A. Bohr p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519 Intrinsically Disordered Proteins and Intrinsically Disordered Protein Regions Christopher J. Oldfield and A. Keith Dunker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 553 Mechanism and Function of Oxidative Reversal of DNA and RNA Methylation Li Shen, Chun-Xiao Song, Chuan He, and Yi Zhang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 585 Progress Toward Synthetic Cells J. Craig Blain and Jack W. Szostak p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 615 PTEN Carolyn A. Worby and Jack E. Dixon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 641 Regulating the Chromatin Landscape: Structural and Mechanistic Perspectives Blaine Bartholomew p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 671 RNA Helicase Proteins as Chaperones and Remodelers Inga Jarmoskaite and Rick Russell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 697
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Selection-Based Discovery of Druglike Macrocyclic Peptides Toby Passioura, Takayuki Katoh, Yuki Goto, and Hiroaki Suga p p p p p p p p p p p p p p p p p p p p p p p p p 727 Small Proteins Can No Longer Be Ignored Gisela Storz, Yuri I. Wolf, and Kumaran S. Ramamurthi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 753 The Scanning Mechanism of Eukaryotic Translation Initiation Alan G. Hinnebusch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 779 Understanding Nucleic Acid–Ion Interactions Jan Lipfert, Sebastian Doniach, Rhiju Das, and Daniel Herschlag p p p p p p p p p p p p p p p p p p p p p p 813
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Indexes Cumulative Index of Contributing Authors, Volumes 79–83 p p p p p p p p p p p p p p p p p p p p p p p p p p p 843 Cumulative Index of Article Titles, Volumes 79–83 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 847 Errata An online log of corrections to Annual Review of Biochemistry articles may be found at http://www.annualreviews.org/errata/biochem
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