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• W1984878710 abstract "While the basics of the conversion of fibrinogen into fibrin have been known for a long time, there has been a great deal of mystery and controversy surrounding the specific binding interactions and the roles of the two major pairs of binding sites. At the present time, some of the binding interactions are finally being characterized by a variety of approaches, although many functional roles are still unclear. When thrombin converts fibrinogen to fibrin, sites exposed in the middle of the molecule by cleavage of its fibrinopeptides bind to sites that are always exposed at the ends of the molecule [1Weisel J.W. Fibrinogen and fibrin.in: Parry DAD Squire J Coiled‐Coils, Collagen and Elastomers. Elsevier, 2005: 247-99Crossref Scopus (637) Google Scholar]. These binding sites have been called knobs and holes, respectively [2Laudano A.P. Doolittle R.F. Synthetic peptide derivatives that bind to fibrinogen and prevent the polymerization of fibrin monomers.Proc Natl Acad Sci USA. 1978; 75: 3085-9Crossref PubMed Google Scholar]. Peptides mimicking the knobs, the amino terminal ends of the α and β chains exposed by thrombin cleavage, were shown to have specific effects on fibrin polymerization. In particular, the GPR sequence resulting from fibrinopeptide A (FpA) cleavage inhibits fibrin polymerization, while the GHR sequence resulting from fibrinopeptide B (FpB) cleavage does not [2Laudano A.P. Doolittle R.F. Synthetic peptide derivatives that bind to fibrinogen and prevent the polymerization of fibrin monomers.Proc Natl Acad Sci USA. 1978; 75: 3085-9Crossref PubMed Google Scholar]. As a matter of definition, cleavage of FpA exposes knobs ‘A’ in the middle of the molecule, which are complementary to holes ‘a’ at the ends, while cleavage of FpB exposes knobs ‘B’, complementary to holes ‘b’. Nearly 30 years after the initial fibrin amino terminal peptide studies, other experiments on the specificity of the peptide binding and the effects of the peptides on fibrinolysis suggest a role of the B:b interactions in the susceptibility of fibrin to lysis [3Doolittle L.R. Pandi L. Binding of synthetic B knobs to fibrinogen changes the character of fibrin and inhibits its ability to activate tissue plasminogen activator and its destruction by plasmin.Biochemistry. 2006; 45: 2657-67Crossref PubMed Scopus (40) Google Scholar, 4Doolittle L.R. Pandi L. The beta‐chain hole of fibrinogen with synthetic peptides that differ in their amino termini.Biochemistry. 2007; 46: 10033-8Crossref PubMed Scopus (17) Google Scholar]. Structural studies have provided much evidence relating to some functions of different regions of fibrin(ogen). Both hole ‘a’ and hole ‘b’ have been visualized at the atomic level [5Spraggon G. Everse S.J. Doolittle R.F. Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin.Nature. 1997; 389: 455-62Crossref PubMed Scopus (392) Google Scholar, 6Yang Z. Mochalkin I. Doolittle L.R. A model for fibrin formation based on crystal structures of fibrinogen and fibrin fragments complexed with specific peptides.Proc Natl Acad Sci U S A. 2000; 97: 14156-61Crossref PubMed Scopus (0) Google Scholar]. Unfortunately, there is no comparable structure for either knob ‘A’ or knob ‘B’, because these regions appear to be flexible and do not show up in the crystal structures. The crystal structures of the end regions of fibrinogen, called fragment D with various GPR‐ or GHR‐containing peptides bound, have shown binding interactions in exquisite detail at the atomic level: GPR peptides fit into holes ‘a’ while GHR peptides fit into holes ‘b’. These are the interactions that have been proposed to occur in fibrin, although the peptides are capable of fitting into the opposite holes under certain circumstances. However, we do not know whether the interactions of these peptides represent the entire binding sites or if there could be more extensive regions involved, as suggested by some studies [7Pandya B.V. Gabriel J.L. O’Brien J. Budzynski A.Z. Polymerization site in the beta chain of fibrin: Mapping of the Bbeta1‐55 sequence.Biochemistry. 1991; 30: 162-8Crossref PubMed Scopus (0) Google Scholar, 8Moen J.L. Gorkun O.V. Weisel J.W. Lord S.T. Recombinant BbetaArg14His fibrinogen implies participation of N‐terminus of Bbeta chain in desA fibrin polymerization.Blood. 2003; 102: 2466-71Crossref PubMed Scopus (0) Google Scholar]. With respect to B:b interactions, the structural studies have posed a challenging puzzle. A model for fibrinogen structure first showed that the C‐terminal β chains of fibrinogen were folded back away from the ends of the molecule [9Weisel J.W. Stauffacher C.V. Bullitt E. Cohen C. A model for fibrinogen: domains and sequence.Science. 1985; 230: 1388-91Crossref PubMed Google Scholar]. X‐ray crystal structures of fibrinogen fragment D confirmed this model and revealed that the holes ‘a’ were at the molecular ends and hence at the location expected to interact with the knobs ‘A’ in the central region of the adjacent molecule of the half‐staggered protofibril (Fig. 1) [5Spraggon G. Everse S.J. Doolittle R.F. Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin.Nature. 1997; 389: 455-62Crossref PubMed Scopus (392) Google Scholar]. However, the holes ‘b’ were far from the ends of the molecule (about 8–9 nm), making their proposed role in B:b interactions more problematic. It is essentially no help to suppose that the B:b interactions could be between protofibrils rather than within a protofibril, as we know that protofibrils must be assembled in register with the 22.5 nm repeat, from the longitudinal order observed in the fibrin structure by electron microscopy and X‐ray fiber diffraction. However, the amino terminal ends of the β chains of fibrin are long enough to act as ‘crab claws’ to span the distance [6Yang Z. Mochalkin I. Doolittle L.R. A model for fibrin formation based on crystal structures of fibrinogen and fibrin fragments complexed with specific peptides.Proc Natl Acad Sci U S A. 2000; 97: 14156-61Crossref PubMed Scopus (0) Google Scholar]. Some molecular modeling studies suggest that such interactions could occur [10Pechik I. Yakovlev S. Mosesson M.W. Gilliland G.L. Medved L. Structural basis for sequential cleavage of fibrinopeptides upon fibrin assembly.Biochemistry. 2006; 45: 3588-97Crossref PubMed Scopus (66) Google Scholar]. An influential proposal hypothesized that the A:a interactions were responsible for protofibril formation while B:b interactions were responsible for the lateral aggregation of the protofibrils necessary for fiber growth [11Blombäck B. Hessel B. Hogg D. Therkildsen L. A two‐step fibrinogen‐fibrin transition in blood coagulation.Nature. 1978; 275: 501-5Crossref PubMed Google Scholar]. Consistent with this model, with purified fibrinogen FpA is cleaved more rapidly than FpB, and cleavage of both fibrinopeptides yields clots composed of thicker fibers. Experiments with snake venom enzymes that preferentially cleave FpA or FpB have provided a great deal of information about functional effects of the binding interactions. With cleavage of only FpA, normal‐looking fibers are still produced, although the fiber diameters are smaller [12Weisel J.W. Fibrin assembly. Lateral aggregation and the role of the two pairs of fibrinopeptides.Biophys J. 1986; 50: 1079-93Abstract Full Text PDF PubMed Google Scholar]. In other words, with only A:a bonds and no B:b bonds, protofibrils are formed and these protofibrils aggregate laterally to make fibers. Thus, B:b interactions are not necessary for lateral aggregation, as originally proposed by Blomback et al. [11Blombäck B. Hessel B. Hogg D. Therkildsen L. A two‐step fibrinogen‐fibrin transition in blood coagulation.Nature. 1978; 275: 501-5Crossref PubMed Google Scholar], but there may still be merit to this model. One question that had been unanswered was whether these B:b knob–hole interactions can actually occur. Experiments with snake venom enzymes that preferentially cleave FpB yield clots at low temperatures, although interpretation of these experiments is complicated by the fact that some cleavage of FpA also occurs, albeit at a slower rate [13Shainoff J.R. Dardik B.N. Fibrinopeptide B and aggregation of fibrinogen.Science. 1979; 204: 200-2Crossref PubMed Google Scholar]. Several recent papers, including two in this issue [14Geer C.B. Tripathy A. Schoenfisch M.H. Lord S.T. Gorkun O.V. Role of ‘B‐b’ knob‐hole interactions in fibrin binding to adsorbed fibrinogen.J Thromb Haemost. 2007; 5: 2344-51Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 15Okumura N. Terasawa F. Haneishi A. Fujihara N. Hirota‐Kawadobora M. Yamauchi K. Ota H. Lord S.T. B:b interactions are essential for polymerization of variant fibrinogens with impaired holes ‘a’.J Thromb Haemost. 2007; 5: 2352-9Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar], demonstrate that these interactions really can occur. First, studies with laser tweezers characterized the strength of the A:a interactions that occur between individual protein molecules or fragments [16Litvinov R.I. Gorkun O.V. Owen S.F. Shuman H. Weisel J.W. Polymerization of fibrin: specificity, strength, and stability of knob‐hole interactions studied at the single‐molecule level.Blood. 2005; 106: 2944-51Crossref PubMed Scopus (0) Google Scholar], and showed that B:b interactions can occur under conditions when A:a interactions could not [17Litvinov R.I. Gorkun O.V. Galanakis D.K. Yakovlev S. Medved L. Shuman H. Weisel J.W. Polymerization of fibrin: Direct observation and quantification of individual B:b knob‐hole interactions.Blood. 2007; 109: 130-8Crossref PubMed Scopus (0) Google Scholar]. Now, in one paper in this issue [14Geer C.B. Tripathy A. Schoenfisch M.H. Lord S.T. Gorkun O.V. Role of ‘B‐b’ knob‐hole interactions in fibrin binding to adsorbed fibrinogen.J Thromb Haemost. 2007; 5: 2344-51Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], the affinities of either isolated A:a or combined A:a and B:b binding sites were measured using surface plasmon resonance. Although Kd were not significantly different, peptide inhibition studies suggested that B:b interactions can occur, although they must be significantly weaker and less stable than the A:a interactions. These experiments, under equilibrium conditions, demonstrate that both A:a and B:b bonds can occur at the same time. Furthermore, the observation that both sets of interactions can occur simultaneously suggests, but does not prove, that they can occur between the same two fibrin molecules and are thus within a single protofibril. Some differences between the laser tweezers and surface plasmon resonance results are likely a consequence of the difference between non‐equilibrium and equilibrium conditions and suggest that the B:b binding may be slower. In conclusion, it is now clear that B:b interactions can occur and the relative strength of that binding is approximately known. In light of this important new information about fibrin polymerization, it may be appropriate to summarize what else we know about this process and what still remains to be discovered. Another major question is whether or not B:b interactions observed in protein model systems actually do occur in fibrin. Although the results of experiments using a snake venom protease to cleave FpB preferentially are ambiguous, there are dysfibrinogenemias (Metz and Frankfurt XIII) in which all fibrinogen molecules are homodimers from which FpA cannot, but FpB can, be cleaved [18Mosesson M.W. DiOrio J.P. Müller M.F. Shainoff J.R. Siebenlist K.R. Amrani D.L. Homandberg G.A. Soria J. Soria C. Samama M. Studies on the ultrastructure of fibrin lacking fibrinopeptide B (beta‐fibrin).Blood. 1987; 69: 1073-81Crossref PubMed Google Scholar, 19Galanakis D. Spitzer S. Scharrer I. Unusual A alpha 16Arg‐‐>Cys dysfibrinogenaemic family: absence of normal A alpha‐chains in fibrinogen from two of four heterozygous siblings.Blood Coagul Fibrinolysis. 1993; 4: 67-71Crossref PubMed Google Scholar]. Remarkably, at low temperatures with thrombin these fibrinogens still form clots, which are made up of thin fibers. In addition, another paper in this issue [15Okumura N. Terasawa F. Haneishi A. Fujihara N. Hirota‐Kawadobora M. Yamauchi K. Ota H. Lord S.T. B:b interactions are essential for polymerization of variant fibrinogens with impaired holes ‘a’.J Thromb Haemost. 2007; 5: 2352-9Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] describes recent experiments with recombinant fibrinogens, γ364 mutants, which have no functional holes ‘a’. There is no polymerization of these mutants with reptilase, which cleaves only FpA, but thrombin cleavage leads to oligomers and eventually to clots that look normal, with thick fibers [15Okumura N. Terasawa F. Haneishi A. Fujihara N. Hirota‐Kawadobora M. Yamauchi K. Ota H. Lord S.T. B:b interactions are essential for polymerization of variant fibrinogens with impaired holes ‘a’.J Thromb Haemost. 2007; 5: 2352-9Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Therefore, it appears that the holes ‘b’ can be utilized without holes ‘a’ to make a clot and that B:b interactions are necessary when A:a interactions are compromised. However, these clots from mutant fibrinogens are formed very slowly and/or are unusual in structure, so that it is still necessary to be cautious about the implications for normal clot formation. In this context, it is worthwhile to remember that under certain circumstances normal fibrinogen (with all fibrinopeptides intact) can polymerize spontaneously to form a clot made up of fibers with a typical fibrin band pattern. Furthermore, do A:b or B:a interactions occur? A:b interactions have been detected in single molecule experiments [17Litvinov R.I. Gorkun O.V. Galanakis D.K. Yakovlev S. Medved L. Shuman H. Weisel J.W. Polymerization of fibrin: Direct observation and quantification of individual B:b knob‐hole interactions.Blood. 2007; 109: 130-8Crossref PubMed Scopus (0) Google Scholar], but the lack of clotting with reptilase (FpA only) cleavage of the γ364 mutants [15Okumura N. Terasawa F. Haneishi A. Fujihara N. Hirota‐Kawadobora M. Yamauchi K. Ota H. Lord S.T. B:b interactions are essential for polymerization of variant fibrinogens with impaired holes ‘a’.J Thromb Haemost. 2007; 5: 2352-9Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] implies that A:b interactions cannot mediate polymerization. In contrast, no B:a interactions have been detected [17Litvinov R.I. Gorkun O.V. Galanakis D.K. Yakovlev S. Medved L. Shuman H. Weisel J.W. Polymerization of fibrin: Direct observation and quantification of individual B:b knob‐hole interactions.Blood. 2007; 109: 130-8Crossref PubMed Scopus (0) Google Scholar]. If B:b or any of these other interactions do occur, are they within or between protofibrils? If we assume that all clots are formed from protofibrils, then these recent experiments with γ364 mutants suggest that B:b interactions are within protofibrils, as proposed many years ago [12Weisel J.W. Fibrin assembly. Lateral aggregation and the role of the two pairs of fibrinopeptides.Biophys J. 1986; 50: 1079-93Abstract Full Text PDF PubMed Google Scholar]. What are the functional roles of B:b interactions in normal fibrin polymerization? Although many potential roles have been suggested, most prominently in lateral aggregation and in fibrinolysis, there is no clear proof for any proposed mechanisms. In particular, there is essentially nothing known about binding sites or mechanisms involved in lateral aggregation, or about branching, although both of these processes are essential to make a functional clot. In addition, it is not clear what is more important for these functional effects: FpB cleavage [20Litvinov R.I. Yakovlev S. Tsurupa G. Gorkun O.V. Medved L. Weisel J.W. Direct evidence for specific interactions of the fibrinogen alpha‐C domains with the central E region and with each other.Biochemistry. 2007; 46: 9133-42Crossref PubMed Scopus (0) Google Scholar], the presence of uncleaved FpB [21Gorkun O.V. Litvinov R.I. Veklich Y.I. Weisel J.W. Interactions mediated by the N‐terminus of fibrinogen’s Bbeta‐chain.Biochemistry. 2006; 45: 14843-52Crossref PubMed Scopus (0) Google Scholar] or the B:b interactions themselves. With purified fibrinogen, thrombin cleaves FpA more rapidly than FpB, with the ordered release of fibrinopeptides dictated by the specificity of thrombin for its substrate [22Mullin J.L. Gorkun O.V. Binnie C.G. Lord S.T. Recombinant fibrinogen studies reveal that thrombin specificity dictates order of fibrinopeptide release.J Biol Chem. 2000; 275: 25239-46Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. It appears that FpB cleavage is enhanced by oligomer formation, but it is not known if oligomers are necessary, and the potential mechanisms remain unknown. Furthermore, it has been reported that FpB is released more rapidly in whole blood than from purified fibrinogen [23Blomback B. Bark N. Fibrinopeptides and fibrin gel structure.Biophys J. 2004; 112: 147-51Google Scholar], although there is considerable evidence for the opposite conclusion [24Brummel K.E. Butenas S. Mann K.G. An integrated study of fibrinogen during blood coagulation.J Biol Chem. 1999; 274: 22862-70Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar]. A conformational change accompanies the binding of GHR to the hole ‘b’ and one of the binding sites for calcium ion is disrupted [25Everse S.J. Spraggon G. Veerapandian L. Doolittle R.F. Conformational changes in fragments D and double‐D from human fibrin(ogen) upon binding the peptide ligand Gly‐His‐Arg‐Pro‐amide.Biochemistry. 1999; 38: 2941-6Crossref PubMed Scopus (0) Google Scholar, 26Kostelansky M.S. Betts L. Gorkun O.V. Lord S.T. 2.8 A crystal structures of recombinant fibrinogen fragment D with and without two peptide ligands: GHRP binding to the ‘b’ site disrupts its nearby calcium‐binding site.Biochemistry. 2002; 41: 12124-32Crossref PubMed Scopus (0) Google Scholar, 27Kostelansky M.S. Lounes K.C. Ping L.F. Dickerson S.K. Gorkun O.V. Lord S.T. Calcium‐binding site beta 2, adjacent to the ‘b’ polymerization site, modulates lateral aggregation of protofibrils during fibrin polymerization.Biochemistry. 2004; 43: 2475-83Crossref PubMed Scopus (0) Google Scholar], which may be important for lateral aggregation. The functional consequences of these observations are largely unknown. In summary, these recent studies demonstrate that knob ‘B’ can bind to hole ‘b’ and clots can be made via these interactions. Next, it will be necessary to determine the functional roles of these B:b interactions in fibrin, along with a host of other related questions about fibrin polymerization. The author states that he has no conflict of interest. I thank R.I. Litvinov and K.E. Edmondson for helpful comments and suggestions and NIH HL30954 for support of research in my laboratory." @default.
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• W1984878710 title "Which knobs fit into which holes in fibrin polymerization?" @default.
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