Localization of a fibrin polymerization site complementary to Gly‐His‐Arg sequence

Medved, Leonid; Litvinovich, Sergei V.; Ugarova, Tatiana P.; Lukinova, Nina; Kalikhevich, V. N.; Ardemasova, Z. A.

doi:10.1016/0014-5793(93)80594-k

Cited by 27 publications

(20 citation statements)

References 16 publications

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“…Thus, synthetic Gly-Pro-Arg peptides do not bind to fragment D in which the -chain is intact but in which the γ-chain has been degraded at the carboxyl end (4,5). Also, photoaffinity labeling experiments with Gly-Pro-Arg derivative peptides led to the exclusive labeling of Tyr γ363 (6,7).…”

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confidence: 86%

Crystal Structure of Fragment Double-D from Human Fibrin with Two Different Bound Ligands^,

et al. 1998

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Factor XIII-cross-linked fragment D (double-D) from human fibrin was crystallized in the presence of two different peptide ligands and the X-ray structure determined at 2.3 A. The peptide Gly-Pro-Arg-Pro-amide, which is an analogue of the knob exposed by the thrombin-catalyzed removal of fibrinopeptide A, was found to reside in the gamma-chain holes, and the peptide Gly-His-Arg-Pro-amide, which corresponds to the beta-chain knob, was found in the homologous beta-chain holes. The structure shows for the first time that the beta-chain knob does indeed bind to a homologous hole on the beta-chain. The gamma- and beta-chain holes are structurally very similar, and it is remarkable they are able to distinguish between these two peptides that differ by a single amino acid. Additionally, we have found that the beta-chain domain, like its gamma-chain counterpart, binds calcium.

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confidence: 86%

Crystal Structure of Fragment Double-D from Human Fibrin with Two Different Bound Ligands^,

et al. 1998

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“…It is unclear by what molecular mechanism FpB release affects polymerization, although a commonly accepted model proposes that FpB is released from growing protofibrils, enhancing the assembly of protofibrils into fibers (5)(6)(7). Release of FpB exposes the "B" polymerization site that binds to the "b" site (2), which may be located in the B␤ chain (8,9) or the A␣ chain (10). In vivo, the result of fibrin polymerization is an intricate fibrous network that, along with platelets, forms a hemostatic plug (11).…”

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confidence: 99%

Recombinant Fibrinogen Vlissingen/Frankfurt IV

Hogan¹,

Gorkun²,

Lounes³

et al. 2000

Journal of Biological Chemistry

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We synthesized a variant, recombinant fibrinogen modeled after the heterozygous dysfibrinogen Vlissingen/Frankfurt IV, a deletion of two residues, ␥Asn-319 and ␥Asp-320, located within the high affinity calciumbinding pocket. Turbidity studies showed no evidence of fibrin polymerization, although size exclusion chromatography, transmission electron microscopy, and dynamic light scattering studies showed small aggregates. These aggregates did not resemble normal protofibrils nor did they clot. Fibrinopeptide A release was normal, whereas fibrinopeptide B release was delayed approximately 3-fold. Plasmin cleavage of this fibrinogen was not changed by the presence of calcium or Gly-Pro-ArgPro, indicating that both the calcium-binding site and the "a" polymerization site were non-functional. We conclude that the loss of normal polymerization was due to the lack of "A-a" interactions. Moreover, functions associated with the C-terminal end of the ␥ chain, such as platelet aggregation and factor XIII cross-linking, were also disrupted, suggesting that this deletion of two residues affected the overall structure of the C-terminal domain of the ␥ chain.Fibrinogen is a 340-kDa glycoprotein that consists of six polypeptides chains, (A␣, B␤, and ␥) 2 . The molecule is symmetric, consisting of two globular D nodules connected to a central E nodule by a coiled-coil region (1). The D nodule consists of a portion of the coiled-coil region and the C termini of both the B␤ and ␥ chains, whereas the E nodule consists of the N termini of all six polypeptides. Thrombin cleaves the N termini of both the A␣ and the B␤ chains, releasing fibrinopeptides A (FpA) 1 and B (FpB) and producing fibrin monomers that polymerize to form a fibrin clot. FpA is released first, exposing the polymerization site "A" that binds to the polymerization site "a" in the ␥ chain in the D domain of another molecule (2). This "A-a" interaction allows molecules to align into double-stranded, half-staggered protofibrils (3, 4). It is unclear by what molecular mechanism FpB release affects polymerization, although a commonly accepted model proposes that FpB is released from growing protofibrils, enhancing the assembly of protofibrils into fibers (5-7). Release of FpB exposes the "B" polymerization site that binds to the "b" site (2), which may be located in the B␤ chain (8, 9) or the A␣ chain (10). In vivo, the result of fibrin polymerization is an intricate fibrous network that, along with plate-

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“…on May 11, 2018. by guest www.bloodjournal.org From that B-knob-mediated interactions are not necessary for protofibril formation or for their lateral aggregation. On the other hand, the surmise about the existence of B:b interactions and their importance for lateral aggregation is based on a great deal of indirect, but consistent, data that can be roughly segregated into 3 groups: (1) differences in clot formation dynamics and structure after selective release of FpA or FpB 16-23 ; (2) binding of GHRP or its derivatives to fibrin(ogen) and their fragments and effects of the peptide(s) on fibrin formation 8,15,[24][25][26][27][28][29] ; (3) consequences of naturally occurring or recombinant mutations of B-knobs or b-holes for fibrinogen conversion to fibrin. [30][31][32] Perhaps the most significant, though not absolute, argument in favor of the occurrence of B:b and other B-knob-mediated interactions during fibrin polymerization is the formation of clots, at 15°C or lower, from desB-fibrin.…”

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confidence: 99%

Polymerization of fibrin: direct observation and quantification of individual B:b knob-hole interactions

Litvinov¹,

Gorkun

Galanakis

et al. 2006

Blood

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The polymerization of fibrin occurs primarily through interactions between N-terminal A-and B-knobs, which are exposed by the cleavage of fibrinopeptides A and B, respectively, and between corresponding a-and b-holes in the-and-modules. Of the potential knob-hole interactions-A:a, B:b, A:b, and B:a-the first has been shown to be critical for fibrin formation, but the roles of the others have remained elusive. Using laser tweezers-based force spectroscopy, we observed and quantified individual B:b and A:b interactions. Both desA-fibrin with exposed A-knobs and desB-fibrin bearing B-knobs interacted with fragment D from the D364H fibrinogen containing b-holes but no functional a-holes. The strength of single B:b interactions was found to be 15 to 20 pN, approximately 6-fold weaker than A:a interactions. B:b binding was abrogated by B-knob mi-metic peptide, the (15-66) 2 fragment containing 2 B-knobs, and a monoclonal anti-body against the 15-21 sequence. The interaction of desB-fibrin with fragment D containing a-and b-holes produced the same forces that were insensitive to A-knob mimetic peptide, suggesting that B:a interactions were absent. These results directly demonstrate for the first time B:b binding mediated by natural B-knobs exposed in a fibrin monomer. (Blood. 2007;109:130-138)

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Localization of a fibrin polymerization site complementary to Gly‐His‐Arg sequence

Cited by 27 publications

References 16 publications

Crystal Structure of Fragment Double-D from Human Fibrin with Two Different Bound Ligands^,

Crystal Structure of Fragment Double-D from Human Fibrin with Two Different Bound Ligands^,

Recombinant Fibrinogen Vlissingen/Frankfurt IV

Polymerization of fibrin: direct observation and quantification of individual B:b knob-hole interactions

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Localization of a fibrin polymerization site complementary to Gly‐His‐Arg sequence

Cited by 27 publications

References 16 publications

Crystal Structure of Fragment Double-D from Human Fibrin with Two Different Bound Ligands,

Crystal Structure of Fragment Double-D from Human Fibrin with Two Different Bound Ligands,

Recombinant Fibrinogen Vlissingen/Frankfurt IV

Polymerization of fibrin: direct observation and quantification of individual B:b knob-hole interactions

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Crystal Structure of Fragment Double-D from Human Fibrin with Two Different Bound Ligands^,

Crystal Structure of Fragment Double-D from Human Fibrin with Two Different Bound Ligands^,