Molecular Microbiology {1992) 6(18), 2549-2555

MicroReview DNA curving and bending in protein-DNA recognition Rodney E. Harrington Department of Biochemistry and Molecular Biology. University of Nevada Reno, Reno, Nevada 89557. USA. Summary Most biological events are regulated at the molecular level by site-specific associations between specialized proteins and DNA. These associations may bring distal regions of the genome into functional contact or may lead to the formation of targe multisubunit complexes capable of regulating highly site-specific transactional events. It is now believed that sequence-specific protein-DNA recognition and the ability of certain proteins to compete for multiple binding sites is regulated at several levels by the local structure and conformation of the binding partners. These encompass the microstructure of DNA, including its curvature, bending and flexing as well as conformational lability in the DNA-binding domains of the proteins. Possible mechanisms for binding specificity are discussed in the context of specific nucleoprotein systems with particular emphasis given to the roles of DNA conformations in these interactions.

evidence for a remarkable range of indirect readout mechanisms has accumulated more recently from crystallographic. spectroscopic, gel, enzymatic and other biochemical studies. It now seems virtually certain that each specific nucleoprotein complex utilizes a characteristic and probably unique combination of direct and indirect recognition mechanisms. Almost all specific nucleoprotein complexes must utilize conformational lability in both the protein and DNA components to improve direct recognition {reviewed by Nussinov, 1990). The specific sequence-dependent structure of the DNA-recognition region is undoubtedly also a factor in many cases (Steitz, 1990). Classes of specific binding proteins may exist whose sole function is to bend DNA to improve recognition and to steer it into the correct trajectory in large, multisubunit complexes. Finally, dynamic effects such as on-off binding kinetics and rates of conformational change as binding partners interact are emerging as possible factors both in Indirect recognition and in the competition of several proteins for the same operator site. These may be controlled both by energetic considerations and by local diffusion. Such an extraordinary level of complexity in nucleoprotein binding, and the interplay of multiple chemical and physical mechanisms, is probably necessary to achieve the required level of site specificity and to reduce errors to a genetically acceptable level in highly site-specific transactional events.

Perspective The ability of certain proteins to recognize specific regions of DNA leading to the self assembly of nucleoprotein association structures of varying degrees of complexity is a complicated and subtle phenomenon. As information has become available, our perception of this ability has progressed through a series of evolutionary stages in the past few years. The notion of direct recognition, in which amino acid residues on a recognition a-helix or [iribbon interact by hydrogen bonding with appropriate bases properly positioned in the major groove of DNA, remains the basis of sequence specificity. However, this idea, originally articulated in the early 1980s by Matthews and coworkers (Anderson et ai, 1981; 1982) on the basis of modelling studies of Cro protein fitted to uniform, Watson-Crick DNA, has required extensive modification as

Received 23 March. 1992: revised and accepted 20 May, 1992. Tel. {702) 7844112; Fax (702) 784 1419,

Specific protein-DNA interactions and their physical nature Regulatory proteins that bind DNA are extremely important as control elements in transcription, replication and certain types of recombination in living organisms ranging all the way from viruses to higher eukaryotes. Many regulatory proteins bind special DNA sequences with extraordinary specificity. Such specific binding is typically =10^ times stronger than non-specific binding of the same protein to other {non-operator) DNA sequences, although non-specific complexes of many regulatory proteins can be formed in vitro. In some instances, the latter may possess biological functionality, but most transactional processes are highly site specific. Therefore exquisitely selective mechanisms for positioning critical nucleoprotein complexes at specific genomic loci have evolved. A common feature of these complexes is very specific

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R. E. Harrington Protein surfaces and DNA helices both possess sequence-dependent topographical variability; binding between the two will depend upon the "goodness of fit' between specific regions of each partner as determined by their sequences. In particular. B-form DNA shows considerable sequence-directed structural variability (Dickerson and Drew, 1981; Dickerson, 1989) which can be manifested as variability in conformation or molecular shape (Bolshoy ef ai., 1991; McNamara and Harrington, 1991). Furthermore, this variability can lead to longerrange structural features such as fixed bends. It has been known for some time that significant DNA curvature is associated with A^ runs, where n is greater than =5 (Marini etaL, 1982; 1983; reviewed in Hagerman. 1990) phased with the same periodicity as the helical repeat. Each poly-A tract is supposed to be associated with DNA curvature either because the axial deflections of successive AA dinucleotides combine coherently to produce a planar curve (Trifonov and Sussman. 1980; Trifonov and Ulanovsky, 1988; Zhurkin, 1985; Zhurkin et al.,

Fig. 1. Illuslration of DNA sequences containing no poly-adenine runs but which nevertheless demonstrate sequence-directed curvature. The computer modelling was performed by Dr S. Ho (Oregon State University, Corvallis, OR, USA) using experimental wedge angles determined by Bolshoy elal. (1990), Retardation factors from gel mobility shift assays FIL = 'W^pp«,,.-./ M-ut- {where M is molecular weight) are from McNamara and Harrington (1991). A. The sequence 5'-GGAGAGCTCACACGACTAGTC-3' viewed in the plane of maximum curvature Ri = i.19. B, C. The sequence 5'-CTCCGGATAGGCTCCGGATAG-3' viewed (C) in the plane o( maximum curvature, and (B) at right angles to the plane of maximum curvature. RL = 1.08,

hydrogen bonding between amino acid residues, most often in a-he!ical or occasionally [i-ribbon (Kim, 1992) 'recognition' regions in the DNA-binding domain of the protein, and nitrogen or phosphate groups constituting a 'recognition matrix' of complementary hydrogen-bonding sites on the DNA. The precise steric matching of these protein-DNA hydrogen-bonding interactions has been termed 'direct readout' (Drew and Travers. 1985a) and certainly constitutes an important component of binding specificity. The requisite structural fit which allows these highly specific interactions to occur, and which itself may make additional contributions to the binding energy, has been called 'indirect readout'. Until fairly recently, it was assumed that this could be understood as a complementary assembly of fixed protein and nucleic acid structures.

1991) or because axial deflections arise from structural discontinuities at the junction of the poly-A tracts assumed to be in a modified B-form structure (Nelson et al., 1987) with adjacent B-form DNA (Koo etal.. 1986); the phasing of the tracts assures that the individual curvatures add coherently to produce a planar overall bend. Phased poly-A regions have been found in many provocative genomic regions (Sundaralingam and Sekharudu. 1988; Hagerman, 1990) Including the minirings of the Leishmania tarentolae kinetoplast in which they were first observed (Challberg and Englund, 1980; Marini ef a/., 1982; 1983). Recent studies have shown that sequence-directed DNA curvature is a general phenomenon and is not limited to sequences containing poly-A runs. A number of curving fragments whose sequences contain no poly-A have been investigated, although the effect is less pronounced than in poly-A-containing regions (Bolshoy etai. 1991; McNamara and Harrington. 1991). Two examples of non-poly-A sequences which exhibit almost planar curvature are shown in Fig. 1. It is likely that sequencedependent DNA structure including coherent effects leading to planar curvature is an important component of indirect readout. DNA bending may be particularly important in facilitating or modulating looping between regulatory elements acting /n c/s at a distance (Ptashne. 1986a) or in the architecture of multisubunit regulatory nucleoprotein complexes (Echols, 1986). The first of these may include the interactions of enhancers with promoter regions, various protein-mediated intrapromoter associations (Elgin, 1988). and effects of chromatin structure on transcriptional regulation (Felsenfeld. 1992). Coherent bending of the DNA results if directional changes in the helical axis are propagated repetitiously in

DNA bending roughly the same plane over a distance of several base pairs. Considerable evidence is now available that DNA bending is associated with many DNA-recognition sequences when bound to specific binding proteins (reviewed by Travers, 1989; Steitz, 1990). Examples of this phenomenon are increasingly being found in eukaryotic systems as well as in helix-turn-helix binding motifs characteristic of many prokaryotic regulators (reviewed by Harrison and Aggarwal, 1990), although there are likely to be many microstructural mechanisms that can lead to bending in the DNA-recognition region as a response to interactions with the complementary protein. DNA in the B form has a relatively high level of conformational lability, and this may help to explain the fact that the Structures of DNA-recognition regions in all nucleoprotein complexes so far investigated are in some variant of the B family (Steitz, 1990). A-form and Z-form DNA are much more conformationally restricted (Saenger, 1983). The structural and conformational accommodations between a specific binding protein and its DNA-binding site are directed by a complex interplay of intermolecular and intramolecular electrostatic and hydrophobic forces. These interactions are non-specific in themselves, but are strongly dependent upon conformational features of the DNA and the correctly folded protein domain. In other words, both the protein and DNA partners seek regions of the other that maximize these interactions, but conformational distortions may also be required to achieve this optimum fit. Binding specificity can occur when these two factors concurrently lead to the formation of specific hydrogen-bond ing contacts. Since these conformational and energetic requirements will generally not be met except at a juxtaposition of critical sequences in both binding partners, the high binding specificity observed between specific binding proteins and their relatively short cognate DNA sequences can be understood. It is becoming increasingly clear, however, that a picture based upon static structures alone is insufficient to explain indirect readout. Evidence is emerging that there is also a dynamic component and that specific proteinDNA binding is also influenced by conformational deformations of both the protein and the DNA. In double-helical DNA, these contormational adjustments may involve highly localized changes in helical twist angles and in the direction of the helical axis at the dinucleotide level. In most cases where specific binding is tight, the net binding free energy will be strongly negative and the equilibrium between unbound species and the bound complex will be shifted well towards the complex. However, some specific binding proteins may be able to discriminate between several similar DNA-binding sites on the basis of the kinetics of one or more steps in the binding mechanism. Such rate-limiting steps would probably involve conformational distortions of the DNA- or protein-binding part-

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ners. Kinetic restrictions could then be imposed either by energy barriers to an intermediate 'transition state' or by the rate of local diffusion.

DNA bending in the helix-turn-helix binding motif Relatively detailed structural information from X-ray crystallography is now available for a number of helix-turnhelix proteins bound specifically to their operator DNA sequences. These include Cro (Brennan etal.. 1991) and the lambda repressor (Jordon and Pabo. 1988) from X phage, the 434 repressor (Ptashne et al., 1980) from phage 434 and the CAP (catabolite gene activator protein) protein from Escheriehia coli (Schultz et al., 1991; Steitz, 1990). The crystallographic results show negligible DNA bending in X repressor, only very gentle bending in the 434 repressor (which is distributed fairly uniformly along the operator site), but definite and distinct bending in the Cro and CAP protein complexes. DNA bending by the latter two proteins has also been examined in solution using gel electrophoresis. Lyubchenko et al. (1991) obtained a bending angle of =45° for Cro complexed to the OR3 binding site by comparing the relative cyclization efficiencies of different sized DNA fragments, each of which was a multimer of a 21 bp helically phased fragment containing the proteinoperator complex. Zinkel and Crothers (1987; 1990) used cyclic permutation of the putative bending locus through a longer sequence combined with a gel mobility shift (CPGMS) assay (Wu and Crothers, 1984) to show that the CAP operator site is bent by =90" in the complex. Both are in excellent agreement with the respective crystallographic results. Crystallographic results have not yet provided the precise locus of bending in Cro (Brennan etal., 1991), but the crystallographic structure of CAP complexed with its operator site shows that the two CA dinucleotide elements kink through =45°; since there are two such elements in the operator site, spaced very nearly at the helical repeat distance, the helical axis bends by =90° (Schultz et al., 1991). Very recent unpublished results from this laboratory on single-site mutations and mismatches of the OR3 site, based upon the thermodynamic criteria for specific binding provided by Takeda et al. (1989), suggest that the single CA element in this site kinks similarly upon specific Cro binding. If the CA element kinks through about the same angle in both CAP and Cro, this would account for the observed magnitude of bending in the latter. The Cro protein is a small (14.7 kDa) protein that binds specifically and non-co-operatively to several binding sites in the >. phage genome. It competes with the X repressor for the 17 bp ORI , OR2 and OR3 sites to effect

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the switch between the lytic and lysogenic modes in this system. The X repressor contains distinct DNA-binding (W-terminal) and protein-binding (C-terminal) domains and binds co-operatively to these same sites and to three additional OLH sites. Its binding affinity to operator sites is somewhat greater than Cro (Ptashne. 1986b). The differences in apparent binding geometry between Cro and A, repressor are not clear. It is possible that kinetic differences in binding due to DNA bending in Cro and co-operative interactions of C-terminal domains in k repressor may play a role in the binding competition between these proteins in the lytic-lysogenic switch mechanism. These questions remain to be resolved. The CAP protein (also called the cyclic AMP receptor protein, CRP) from E co//functions primarily as an activator of transcription although it can also act as a repressor (de Crombrugghe et al., 1984). If carbon sources are restricted, several operons including lac and gal are induced so that alternative sugars can be catabolized using the coded enzymes. When CAP binds to its allosteric effector cAMP, it actuates transcription in =20 promoters in E. coli (de Crombrugghe et al.. 1984) located from 41 to 103 bp upstream from the start site. The complex binds as a dimer to a 16 bp consensus sequence 5'-TGTGANNNNNNTCACA-3'. The strongest binding is to the lacPI promoter having the sequence 5'TGTGAGTTAGCTCACT-3', but the characteristic alternating purine-pyrimidine motif, especially the CAC/GTG triplet, appears to be a common feature of most CAPbinding sites (Barber and Zhurkin, 1990). Strong binding interactions occur over 28 to 30 bp, a region almost twice the size of the consensus sequence (Liu-Johnson et al.. 1986). This appears to require substantial DNA bending in order to maintain contact between the DNA and protein. Although earlier studies implicated sequences outside the consensus region in the bending (Gartenberg and Crothers. 1988), the crystallographic results noted above (Schultz et al., 1991; Steitz, 1990) show that virtually the entire bending can be accounted for in the CA/TG kinks. Residual bending seems to be due to the phased alteration of AT- and CG-rich regions which has also been characterized in nucteosomal DNA bending (Drew and Travers, 1985b). In addition to the helix-turn-helix contacts, the crystal structure shows that recognition is modulated by 13 additional side chains interacting with 11 phosphates covering a total of 28 bp. Thus, the binding interaction has a large non-specific component, but the specific component Is evidently due largely to the unusual DNA conformation. The bending seems also to have a functional significance since sequences with fixed bends can activate the promoter both in vivo (Braoco et al., 1989) and in vitro (Gartenberg and Crothers, 1991). It is likely that CAP'S main functional role in promoter activation, and possibly its only role, is to bend the promoter

DNA to allow formation of the transcription complex (Lilley, 1991; Bracco et ai. 1989). In this case. CAP may be only one of a much larger class of DNA-steering proteins. Other specific binding proteins that bend or change the conformation of DNA The concept that many specific binding proteins may steer DNA through a large multiprotein association complex by bending it precisely at highly specific binding sites receives support from investigations on proteins involved in site-specific recombination in X phage and other systems (reviewed by Echols, 1986, and Nash, 1990). These include the Int, IHF and Xis proteins, all of which are implicated in the formation of large association complexes which confer extremely high precision on site-specific events (Goodman and Nash, 1989; Snyder et ai., 1989). IHF has been shown to bend DNA through an angle of at least =90" when bound to each of its three specific binding sites in the X phage attP recombination region (Robertson and Nash, 1988; Thompson and Landy, 1988). Other proteins that impart large bending angles to their DNA-recognition regions include PIS and y6 resolvase (Thompson and Landy, 1988; Salvo and Grindley, 1988). Many eukaryotic regulatory proteins may also bend their DNA-binding sites, although this phenomenon has been demonstrated experimentally only in a limited number of cases. One of these is the archetypal zinc finger protein TFIIIA from Xenopus, required for pol III transcription of 5S ribosomal subunit genes (Engeike et al., 1980). TFIIIA is 39 kDa in size and binds in a highly sequencespecific fashion to a 52 bp internal control region spanning bases 45 to 97 in a 122 bp highly conserved region. DNA binding occurs in a 30 kDa region of the A/-terminal domain (Sakonju et at., 1980; Bogenhagen etal., 1980) which contains nine well-defined zinc fingers (Miller etal.. 1985). On average, therefore, each finger domain can interact with as much as =5 bp. In a binding model proposed by Berg (1988; reviewed by Berg, 1990), the fingers wrap around the major groove making =3 bp contacts. To fit the hydroxyl radical footprint of the complex (Vrana et al.. 1988), fingers 1, 5, 7 and 9 lie in the major groove while 6 is constrained to lie across the DNA because of the short linkers. This requires a kink of =60° or greater in the DNA at a point =1/3 from the end of the internal control region. Experimental evidence on the extent of bending is mixed, although all studies so far seem to indicate some DNA axial deformation. Phosphorus imaging electron microscopy (Bazett-Jones and Brown. 1989) and CPGMS assays (Schroth etal., 1989) are consistent with a bend in the internal control region of =65° in the complex. On the other hand, Zweib and Brown (1990) have reported a bending angle of no more than

DNA bending =30° using similar gel methods. The discrepancy in these results may be due to differences in ionic strength conditions employed (Schroth et ai, 1990) since at high and low ionic strengths TFIIIA may exist in different conformational states which may bend the internal control region differently upon complexation. Other eukaryotic regulatory proteins appear not to bend their DNA recognition sites, however. The large superfamily of hormone receptor proteins which includes the steroid hormone, thyroid hormone, retinoic acid and vitamin D3 receptors (reviewed by Beato, 1989, and Klevit et al.. 1990) evidently have zinc finger motifs that differ significantly from TFIIIA and fold together as part of a single domain (Hard et al.. 1990). The crystal structures of the glucocorticoid receptor protein (Luisi et ai, 1991) and the Zif268 zinc finger protein from mouse (Pavletich and Pabo, 1991) show no evidence of DNA bending in the recognition region. The latter is a three-finger motif protein, and its binding is generally consistent with the Berg model. Thus, as in helix-turn-helix proteins, there is still no comprehensive predictive model for the tendency of zinc finger proteins to bend their DNA-binding sites. The Fos and Jun oncogene proteins are transcription factors that interact either as homodimers or heterodimers with a DNA-binding region that is conserved from yeast to humans (reviewed in Vogt and Bos, 1989). CPGMS assays indicate that both proteins bend the AP-1 consensus binding site, 5'-TGACTCA-3' and phased bending studies suggest that significant conformational change may occur also in the proteins (Kerppola and Curran, 1991a,b). These studies also suggest that binding of Fos-Jun heterodimers and Jun-Jun homodimers direct bending in opposite directions: Fos-Jun binding leads to DNA bending into the major groove whereas Jun-Jun bends DNA towards the minor groove. Other Fos-Jun combinations appear to induce only negligible DNA bending, and it has therefore been postulated that DNA flexibility in the AP-1 site may be influenced by the binding of the proteins (Kerppola and Curran, 1990a). The AP-1 consensus sequence has dyad symmetry about the central CG element and contains CA/TG elements phased at half-helical periodicity. These elements may be favoured kink sites in DNA (McNamara et ai, 1990) and, as noted above, kinking at CA has been shown to occur in the CAP protein-operator complex (Schultz et al.. 1991; Steitz, 1990). Cellular Jun from both chicken and human also bind to a 5'-TGACACA-3' site located between the CAAT box and a TATA-like sequence element; when bound to this site, it functions as a positive autoregulator for the gene (Angel et ai, 1988). This sequence is asymmetric, and if kinking occurs at CA, the change from a CT to a CA element may substantially alter the path of the DNA in the complex. Another group of oncogene regulators that bind to

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palindromic recognition sequences containing (nearly) phased CA elements are the Myc proteins. These bind to 5'-CACGTG-3' consensus sites (Kerkhoff et ai, 1991). They are thought to bind using a helix-loop-helix motif and have characteristic leucine zipper regions which, combined with their palindromic recognition site, suggests that they bind as dimers. This consensus sequence is also recognized by a variety of regulatory proteins including the USF (Sawaddogo et ai, 1988) and TFE3 (Beckmann et al., 1990) transcription factors of the adenovirus major late promoter, the |iE3 in the immunoglobulin heavy-chain enhancer (Kerkhoff et ai, 1991) and the Gbox proteins of plants (Gilmartin etal., 1990). Although at present there is no firm evidence for DNA bending in these systems, it is likely that some structural and conformational dislocation occurs in the recognition site upon binding. Such dislocation may involve kinking at CA/TG sites or may arise from intrastrand hydrogen bonding and a base-pairing frame shift in the major groove, as recently reported in a crystallographic study of alternating (CA)^ tracts (Timsit era/., 1992). A protein that has been shown to bend its DNA recognition region but utilizes a distinctively different recognition mechanism is TFIID, the TATA-binding' protein. TFIID is a transcription factor required for efficient polymerase II activity in many, and perhaps all, protein-encoding genes in eukaryotic cells. It binds to the TATA box, a conserved sequence located =-30 bp upstream from most pol II start sites, and induces the formation of a multiprotein pre-initiation complex that appears to be stable through several rounds of transcription (Buratowski et ai, 1989). It has elements of structural similarity with IHF of E. coli and several other regulatory proteins that may also be reflected in the binding properties (reviewed in Nash and Granston, 1991). Recent studies have indicated that, unlike most regulatory proteins that form specific contacts in the major groove of their recognition sites, TFIID binds in the m/nof groove of the TATA element (Starr and Hawley, 1991; Lee et al., 1991). CPGMS assays have shown that the TATA element DNA is bent in the association complex (Lee etal,, 1991; Horikoshi etal., 1992). It is therefore of interest that the TA dinucleotide has also been implicated as a favoured kink site in DNA (McNamara et ai, 1990). Furthermore, the kinetics of TFIID binding are slow and require thermal energy (Lee et al.. 1991), suggesting that the protein may also undergo a significant conformational change upon binding. Since these proteins evidently nucleate and become elements of larger multiprotein complexes, their conformations and the trajectories of the associated DNA must be subject to severe constraints. These results suggest that the kinetics of binding as influenced by conformational changes in both the DNA and protein may be important in conferring binding specificity, in determining the architecture of large

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multisubunit complexes or in facilitating the space/time juxtaposition of c/s-acting regulatory elements. Further evidence for possible conformation-induced kinetic effects in specific protein-DNA interactions are provided by the binding of NF-KB and its ability to discriminate among a large number of superficially similar recognition sites. NF-KB is a pleiotropic transcription factor that can effect gene control in a highly tissue-specific fashion (reviewed by Lenardo and Baltimore, 1989; Sen and Baltimore. 1986). It has recently been cloned, and analysis of its nucleotide sequence suggests that no zinc finger regions are present (Kieran et ai, 1990; Ghosh et ai. 1990). It binds specifically to at least 11 different -^10 bp consensus sequences, depending upon cell type in various promoter and enhancer regions (Lenardo and Baltimore, 1989). It was originally identified in KB sites of the K light-chain enhancer of B cells and was thought to be functional only in this system (Atchison and Perry. 1987), but later studies have shown that it plays many roles in many cellular systems including T-cell activation, cytokine regulation, and the control of a number of viral systems. Cytomegalovirus (CMV) and SV-40 have NF-tcB binding sites in their enhancers (Siddiqui et ai, 1989), and the HIV-1 enhancer has 2 NF-icB binding sites, one of which regulates transcriptional inducibility of the 5" long terminal repeat in activated T cells (Nabel and Baltimore, 1987). The principal DNA-binding form of NF-KB is a heterotetramer which includes two 50 kDa binding and two nonbinding 65 kDa subunits. The synergistic interaction of these subunits evidently enables the complex to discriminate among a multiplicity of target sites and to control many genes under various biological conditions. The precise discriminatory mechanism employed in this system is not well understood, but some evidence exists that it is based upon DNA bending in spite of the fact that none of the consensus binding sequences show extensive alternating purine-pyrimidine regions. Using the CPGMS assay, Schreck et al. (1990) recently demonstrated an induced bending of =110° at the KB motif, 5'GGGACTTTCC-3'. The locus of bending was near the 3' end. and there appeared to be no minor groove contacts between the protein and the recognition site or other unusual DNA structure as evidenced by Dnase I cleavage patterns. Computer modelling of this site using the predictive scheme of Bolshoy et al. (1990) provides no evidence for significant fixed bending in the DNA in the absence of protein. Comparative binding studies have suggested a sequence of events in which the binding region is contacted first by the 50 kDa subunits followed by DNA bending and contact by the 65 kDa subunits (Urban and Baeuerle. 1991). This suggests that a kinetic mechanism may permit discrimination among the various possible target sequences. This view is further supported by the very low concentrations of NF-KB typically found in cells

(Baeuerle and Baltimore, 1989). Such a kinetic mechanism therefore appears to be potentially as important a mechanism in specific binding as the thermodynamic stability of the complexes, e.g. the binding constants (Urban and Baeuerle, 1991) and may be so also in many other nucleoprotein systems.

Acknowledgements The author gratefully acknowledges stimulating conversations with P- H, Von Hippel, B. W. Matthews, E. Appella, E. N. Trifonov, Y. L. Lyubchenko. L. Shiyakhtenko, V. B. Zhurkin and S. M. Lindsay and financial support from the National Institutes of Health and National Science Foundation.

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DNA curving and bending in protein-DNA recognition.

Most biological events are regulated at the molecular level by site-specific associations between specialized proteins and DNA. These associations may...
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