Studies on synthetic peptides that bind to fibrinogen and prevent fibrin polymerization. Structural requirements, number of binding sites, and species differences

Laudano, Andrew P.; Doolittle, Russell F.

doi:10.1021/bi00546a028

Cited by 286 publications

(248 citation statements)

References 22 publications

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“…Synthetic peptides Gly-Pro-Arg-Pro and Gly-His-Arg-Pro were shown to bind to fibrinogen [2]. They also bind to the D,-fragment [3] which derives from the terminal region of fibrinogen and contains intact C-terminal regions of both p and y chains. The D,-fragment binds Gly-HisArg-Pro but does not bind Gly-Pro-Arg-Pro, indicating that the 13 kDa C-terminal region of the y-chain, missing in the D,-fragment, is involved in the formation of a polymerization site complementary to the latter sequence [4] Less is known about the other polymerization site complementary to the Gly-His-Arg sequence.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1993

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Dansyl-labeled tetrapeptide Gly-His-Arg-Pro which mimics the central fibrin polymerization site was used to investigate its binding to a number of fibrinogen fragments containing different numbers of domains. The tetrapeptide was found to bind to fragments D,(95 kDa), D&32 kDa) and D,(63 kDa) but not to the TSD(28 kDa) fragment. The D, fragment differs from the TSD by the presence of /I and/K domains. Therefore these domains, which are formed by the C-terminal part of the j3 chain, possess a polymerization site complementary to the Gly-His-Arg containing counterpart.

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Section: Introductionmentioning

confidence: 99%

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

et al. 1993

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“…The procoagulant potential of FX (and derivatives) was evaluated by its ability to induce thrombin formation in FX-depleted plasma. Clotting was triggered at 37°C by the addition of 50% (v/v) kinetic buffer containing 40 mM CaCl 2 , 160 M phospholipid vesicles, 0.5 nM TF, and 160 nM FX (or derivatives) to plasma containing 16 mM Gly-Pro-ArgPro-amide to prevent fibrin polymerization (29,30). Particular care was taken to verify that FXa or activated derivatives were undetectable prior to the addition of their zymogens to plasma.…”

Section: Plasma (Ex Vivo) Studies Of Fxa and Derivatives-mentioning

confidence: 99%

“…8). The reaction was started by the addition of a mixture of TF, phospholipid, calcium, and FX (or variant) to plasma containing Gly-Pro-Arg-Pro-amide to prevent fibrin polymerization (29,30). Compared with FX supplementation, the addition of E36Q/E37Q/E39Q or E74Q/E76Q/ E77Q allowed quicker formation of more thrombin, whereas the addition of E36K/E37K/E39K or E74K/E76K/E77K triggered later formation of less thrombin.…”

Section: Figmentioning

confidence: 99%

The Elusive Role of the Potential Factor X Cation-binding Exosite-1 in Substrate and Inhibitor Interactions

Bianchini

Pike

Bonniec

2004

Journal of Biological Chemistry

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Coagulation factor X (FX) 1 is a vitamin K-dependent zymogen activated into FXa by cleavage at a single bond (Arg 15 -Ile 16 in the chymotrypsin numbering system 2 ) hydrolyzed by either of two complexes: FVIIa bound to tissue factor (TF), which triggers coagulation after injury, or FIXa associated with FVIIIa, which amplifies thrombin production after initiation of coagulation. FXa is the only endogenous prothrombin activator, but substantial thrombin production occurs only within the prothrombinase complex, where FXa binds to FVa in the presence of calcium on an appropriate phospholipid surface. Two inhibitors control FXa activity, viz. the tissue factor pathway inhibitor (TFPI) and antithrombin.Extended binding sites (exosites) play a crucial role in virtually any substrate, cofactor, or inhibitor recognition within the coagulation cascade. Perhaps best characterized is the case of thrombin taking advantage of two exosites for extended interactions in numerous functions (1). Exosite-1 is formed by a set of basic residues comprising loops 34 -40 and 70 -80, which neighbor each other in the folded structure (2); it interacts with fibrinogen, thrombomodulin, platelet activator receptor-1, FV, FVa, heparin cofactor II, and hirudin. Exosite-2, comprising loop 91-102 and helices 165-173 and 233-245 (3), is also formed by a set of basic residues that interact with heparin, with the chondroitin sulfate of thrombomodulin, and within prothrombin with kringle-2 (4). In FVII, the region corresponding to exosite-1 of thrombin is critical for FX activation (5, 6); in FIXa, this region is also important for FX activation in the absence of FVIII and for its inhibition by antithrombin in the absence of heparin (7). In contrast to thrombin, FVIIa, FIXa, and FXa share a negatively charged patch within segment 70 -80, whereas FXa is unique in that both loops 34 -40 and 70 -80 are negatively charged. Thus, the region of FXa corresponding to exosite-1 of thrombin forms a negative cluster, raising the question as to whether it could constitute a functional exosite. FXa has a unique macromolecule substrate, but exosites may also participate in its inhibition and/or in the activation of its zymogen. In fact, a number of studies have established that exosite(s) must be critical in several FXa functions. Electrostatic interactions involving loop 34 -40 of FXa appear to play a significant role in binding to the second Kunitz domain of TFPI (8,9). FXa also appears to interact with a complementary surface on pentasaccharide-activated antithrombin (10), and the region of FXa topologically equivalent to exosite-2 of thrombin seems to be involved in the binding of heparin and FVa (11). Above all, prothrombin recognition by prothrombinase undoubtedly involves one or more exosites on .In a previous study (15), we reported that the catalytic groove of FXa is minimally selective with unconstrained peptides and that FVa has little effect, if any, on this selectivity. These two observations therefore also favor the hypothesis that FXa uses seconda...

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“…In 1978, one of my graduate students, Andrew Laudano, synthesized a number of peptides corresponding to the amino-terminal sequences that occur at the newly exposed ends of fibrin. These peptides bound to both fibrinogen and fragments D, and some of them were very effective in blocking polymerization [13]. Moreover, in contrast to the hexamethylene glycol (HMG) that Ferry's group had used to arrest the association of protofibrils, the tetrapeptides were presumably blocking at the very first step of polymerization.…”

Section: Synthetic Peptide Knobsmentioning

confidence: 99%

Some comments on John Ferry's most enduring paper

Doolittle

2004

Biophysical Chemistry

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Studies on synthetic peptides that bind to fibrinogen and prevent fibrin polymerization. Structural requirements, number of binding sites, and species differences

Cited by 286 publications

References 22 publications

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

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

The Elusive Role of the Potential Factor X Cation-binding Exosite-1 in Substrate and Inhibitor Interactions

Some comments on John Ferry's most enduring paper

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