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Lipids and Extracellular Materials William Dowhan Department of Biochemistry and Molecular Biology, University of Texas, Houston, Texas 77030; email: [email protected]

Annu. Rev. Biochem. 2014. 83:45–49

Keywords

First published online as a Review in Advance on March 3, 2014

lipidomics, lipopolysaccharides, multiple-reaction monitoring, heparan sulfate, Kdo2 –lipid A, mass spectrometry, proteoglycans

The Annual Review of Biochemistry is online at biochem.annualreviews.org This article’s doi: 10.1146/annurev-biochem-010314-112017 c 2014 by Annual Reviews. Copyright  All rights reserved

Abstract This article introduces the Lipids and Extracellular Materials theme of the Annual Review of Biochemistry, Volume 83.

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Although the individual topics of this section may appear unconnected, they are quite interrelated. “Topological Regulation of Lipid Balance in Cells” by Guillaume Drin (1) relies heavily on the identification and quantification of lipid species across eukaryotic cell membranes. Current developments in “Lipidomics: Analysis of the Lipid Composition of Cells and Subcellular Organelles by Electrospray Ionization Mass Spectrometry” by Britta Brugger (2) ¨ illustrate the importance of and advances in lipid analysis toward understanding the diversity of lipid species within cells. “Biosynthesis and Export of Bacterial Lipopolysaccharides” by Chris Whitfield and M. Stephen Trent (3) details the synthesis of a macromolecular assembly in the inner membrane of gramnegative bacteria followed by its deposition in the outer membrane. The common core membrane component of lipopolysaccharide (LPS) is a phospholipid for which structural determination and elucidation of its biosynthetic pathway relied heavily on the application of mass spectroscopy. “Demystifying Heparan Sulfate– Protein Interactions” by Ding Xu and Jeffrey D. Esko (4) covers a subset of proteoglycans that are synthesized within internal organelles, followed by transport via the vesicular transport system for final residency on the surface of the cytoplasmic membrane or release to the extracellular space. Heparan sulfate (HS)containing proteoglycans interact with a large number of proteins to affect diverse cellular processes. Drin (1) presents a comprehensive and timely review of the diversity of lipid species within a eukaryotic cell. A brief description of the general lipid classes (phospholipids, sphingolipids, and steroids) is followed by a detailed analysis of the distribution of these lipids along the intercellular vesicular trafficking route from the endoplasmic reticulum to the Golgi apparatus and finally to the plasma membranes. A comprehensive review of mitochondrial lipids of yeast, which is not covered in this presentation, can be found elsewhere (5). With few exceptions, a given protein expressing a unique function is found in only one cellular

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membrane or cell organelle, whereas membrane lipids are distributed over the multiple organelle membranes and both leaflets of lipid bilayers. However, the endoplasmic reticulum, Golgi apparatus, and plasma membranes are distinctly different in their respective compositions of lipids and distribution of lipids between the two leaflets of their lipid bilayers. This review describes differences in lipid distribution over the multiple cellular membranes of eukaryotic cells and discusses the functional and regulatory consequences for lipid synthesis and resident protein function. The multiple functions of lipid transport proteins, and whether they are lipid-sensitive regulatory proteins or true lipid transport proteins, are analyzed. The fact that lipid environment can modify the structure and function of membrane proteins, coupled with the large differences in lipid composition along the secretory pathway or laterally within a single membrane, may explain the increasing number of proteins that display multiple–transmembrane domain organization and function (6). Evidence from whole-cell experiments and purified membrane proteins reconstituted into proteoliposomes demonstrates that initial transmembrane domain orientation with respect to the plane of the lipid bilayer is determined by charge interactions between the protein extramembrane domains and the membrane surface–exposed lipid headgroups (7). Furthermore, once assembled, membrane proteins can undergo topological inversion of their transmembrane domains in response to a change in the lipid environment independently of any additional cellular factors (6). These observations suggest that there is an additional elegant mode of cellular regulation governed solely by the changing lipid environment of proteins along the secretory pathway or spatially and temporally within a given membrane (6, 7). As reviewed by Brugger (2), the contri¨ bution to lipidomics, as a subdiscipline of metabolomics, of recent advances in mass spectrometric analysis of lipids cannot be overstated. The complexity of the lipidome, both structurally and in physical/chemical

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properties, poses much greater challenges to analysis than does genomics or proteomics. A few nucleotides and a few more amino acids, all of similar structure and properties, make up the latter two classes of macromolecules. However, lipids such as phospholipids, neutral lipids, sphingolipids, and steroids possess diverse chemical and physical properties. Each class of lipids includes hundreds to even thousands of subspecies. Brugger provides a brief overview ¨ of the core structure of the various lipid classes found in the different cell membranes, then outlines the challenges to lipidomics in determining and quantifying the diverse classes of lipids by electrospray ionization mass spectrometry (ESI-MS). Major obstacles in the field have been suitable extraction protocols for the many lipid types, resolution of the complex ESI-MS spectra, development of bioinformatic tools, and the availability of molecular standards for quantification of lipid species. The LIPID MAPS consortium (http://www.lipidmaps.org) in the United States, LipidBank (http://www.lipidbank.jp) in Japan, and LipidomicNet (http://www. lipidomicnet.org) in Europe have cooperated to devise classification systems, methodology, and forums for the benefit of researchers. Avanti Polar Lipids (http://avantilipids.com), through subcontracts from LIPID MAPS, has made sets of lipid standards necessary for quantification available to the research community. A powerful analytical technique is tandem MS (MS/MS), in which the subsequent fragmentation products of a primary molecular ion are separated by their mass. Because complex lipids are made up of diverse hydrophilic and hydrophobic building blocks that are displayed after the second fragmentation event, MS/MS is very useful for more detailed analysis of the fatty acid and headgroup composition of phospholipids and sphingolipids. The effective use of MS/MS to establish precursor–product relationships for a number of lipids is described, along with a more extensive use for analyses of cardiolipin and eicosanoid species. Selective or multiple-reaction monitoring (MRM) can provide even more definitive conclusions about

the origin of selective parts of a lipid, even in complex mixtures of primary molecules. In this method, the secondary fragmentation mixture is filtered to display only selective molecular species if they are present. A combination of MS/MS and MRM was essential in establishing a previously unrecognized bacterial pathway for the synthesis of cardiolipin (8). LPS covers more than 70% of the surface of the outer membrane of most but not all gram-negative bacteria. This surface provides a strong permeability barrier and lies at the center of host–pathogen interaction and the ultimate reaction of eukaryotic cells to bacterial infection. Whitfield & Trent (3) first outline the pioneering combination of biochemistry, enzymology, genetics, and structural biology that characterized the nine enzymes responsible for the so-called Raetz pathway leading to the synthesis of the core lipid component (Kdo2 –lipid A) of LPS. The pathway was named in honor of Christian Raetz, whose scientific career and personal life are summarized elsewhere (9). The elucidation of this pathway and its variants by Raetz relied heavily on the use of ESI-MS. Escherichia coli has served as the primary organism for unraveling the synthesis of LPS, which has been the template for studies on variations in other bacteria. The Kdo2 – lipid A structure is highly conserved with some variation across bacterial species, as summarized by the authors. Lipid A triggers the endotoxin proinflammatory response, which can be muted due to the ability of bacteria to modify the lipid A structure. Kdo2 –lipid A and initial addition of a core polysaccharide unit occur on the cytoplasmic face of the inner bacterial membrane, followed by a translocation by the MsbA flippase to the outer surface of this membrane, where the presynthesized outer polysaccharide, composed of 50 to 200 repeating tetrasaccharide units, is added. The outer polysaccharide core, which forms a signature structure for individual bacterial species, is built on an undecaprenol diphosphate carrier exposed to the periplasmic side of the inner membrane. The whole assembly is then transported to the outer surface of the outer membrane by www.annualreviews.org • Lipids and Extracellular Materials

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complex ATP-driven export machinery composed of seven proteins. Because failure at multiple sites along the synthesis of LPS is fatal, this pathway, unique to bacteria, is rich in potential antibacterial targets. Eukaryotic cells also contain a rich mixture of surface antigens that are necessary for normal cell-recognition processes. Among these are the long linear chains of glycosaminoglycans such as HS, which is covalently attached in multiple copies to proteins that make up the mixture of proteoglycans found as cytoplasmic membrane proteins and in the extracellular fluid. Xu & Esko (4) review the “heparan sulfate interactome,” which is composed of HS-binding proteins (HSBPs) that are responsible for cell attachment, migration, invasion, differentiation, morphogenesis, organogenesis, blood coagulation, lipid metabolism, inflammation, and responses to injury. HS is a linear polysaccharide composed of 50 to 250 repeating disaccharide units made up of N-acetyl glucosamine and either glucuronic or iduronic acid, with each unit sulfated to different degrees. Due to the highly anionic character of HS, many proteins nonspecifically bind HS, but approximately 300 proteins have been defined as specific HSBPs on the basis of physiological conditions and extracellular proximity to HS-containing proteoglycans. HSBPs are structurally unrelated, have unrelated binding folds, and possess a wide range of affinities and specificities, all suggesting convergent evolution. As noted above, the wide range of functions associated with HSBPs

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includes recognition by pathogens resulting in infection. The specificity of HSBPs for simple ionic interactions extends to recognition of structural differences along the HS chain. A major function of HS is to tether proteins to a specific location in the extracellular space or on the cell membrane surface. The review outlines multiple aspects of this tethering. An alternative mechanism to organization of molecular machines composed of different functional units is through oligomerization induced by interaction between multiple HSBPs and HS. Such an organization is more dynamic and more responsive to cellular changes than are interactions that depend solely on protein–protein interactions. HS-induced oligomerization occurs with growth factors, in the inflammatory response, with amyloid precursor proteins, and with chemokines. In a related phenomenon, HS provides a scaffold for organization of proteins into larger complexes. Additional examples exist of HS acting as an allosteric effector. A major question in the field involves the level of specificity in the HS–HSBP interaction, which appears to range from a highly specific to a general nonspecific charge interaction, as reviewed by the authors. High-resolution structures are available for a number of HSBPs, which demonstrate the diversity of structural folds responsible for recognition of HS. The study of HSBPs is ripe for further important discoveries, given that only a small fraction of HSBPs have been biochemically or structurally defined. Many HSBPs remain to be discovered with location or temporal specificity.

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. Drin G. 2014. Topological regulation of lipid balance in cells. Annu. Rev. Biochem. 83:51–77 2. Brugger B. 2014. Lipidomics: analysis of the lipid composition of cells and subcellular organelles by elec¨ trospray ionization mass spectrometry. Annu. Rev. Biochem. 83:79–88 3. Whitfield C, Trent MS. 2014. Biosynthesis and export of bacterial lipopolysaccharides. Annu. Rev. Biochem. 83:99–128 48

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4. Xu D, Esko JD. 2014. Demystifying heparan sulfate–protein interactions. Annu. Rev. Biochem. 83:129–57 5. Horvath SE, Daum G. 2013. Lipids of mitochondria. Prog. Lipid Res. 52:590–614 6. Bogdanov M, Dowhan W, Vitrac H. 2014. Lipids and topological rules governing membrane protein assembly. Biochim. Biophys. Acta 286:15182–94 7. Dowhan W, Bogdanov M. 2009. Lipid-dependent membrane protein topogenesis. Annu. Rev. Biochem. 78:515–40 8. Tan BK, Bogdanov M, Zhao J, Dowhan W, Raetz CRH, Guan Z. 2012. Discovery of a cardiolipin synthase utilizing phosphatidylethanolamine and phosphatidylglycerol as substrates. Proc. Natl. Acad. Sci. USA 109:16504–9 9. Dowhan W, Nikaido H, Stubbe J, Kozarich JW, Wickner WT, et al. 2013. Christian Raetz: scientist and friend extraordinaire. Annu. Rev. Biochem. 82:1–24

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Contents

Annual Review of Biochemistry Volume 83, 2014

Annu. Rev. Biochem. 2014.83:45-49. Downloaded from www.annualreviews.org by National University of Singapore on 06/10/14. 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. 2014.83:45-49. Downloaded from www.annualreviews.org by National University of Singapore on 06/10/14. 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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Annual Review of Statistics and Its Application Volume 1 • Online January 2014 • http://statistics.annualreviews.org

Editor: Stephen E. Fienberg, Carnegie Mellon University

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Associate Editors: Nancy Reid, University of Toronto Stephen M. Stigler, University of Chicago The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as well as all scientists and users of statistics about major methodological advances and the computational tools that allow for their implementation. It will include developments in the field of statistics, including theoretical statistical underpinnings of new methodology, as well as developments in specific application domains such as biostatistics and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences.

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• What Is Statistics? Stephen E. Fienberg • A Systematic Statistical Approach to Evaluating Evidence from Observational Studies, David Madigan, Paul E. Stang, Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage, Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema, Patrick B. Ryan

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