The biological effects of the binding of fibrin(ogen) degradation products to M protein-bearing group A streptococci were investigated. Type 24 group A streptococci bind fibrinogen degradation products of the D family, but not fragment E. Binding appears to be mediated by M protein, since a large peptide of this molecule (pep M24) bound to fragments containing the terminal domains of the fibrinogen molecule (D, X, and Y), but not fragment E, and pep M24 inhibited the binding of digested fibrinogen to streptococcal cells. An M protein-binding site occurs on fragment D3 and, therefore, differs from several functional sites present on D1 but not D3, including the fibrin polymerization site, the two gamma chain crosslink sites, and the bindings sites for platelet fibrinogen receptor, staphylococcal clumping factor, and ionized calcium. Bound fibrinogen degradation products prevented deposition of C3 on the streptococcal cell surface, and, in consequence, prevented phagocytosis by neutrophils in nonimmune blood. The average affinity of D fragments for the streptococcal cell surface was approximately 30 times lower than that of native fibrinogen, and a terminal plasmic digest was approximately 50 times less potent in inhibiting opsonization by C3. However, physiologic concentrations of digested fibrinogen sufficed to inhibit opsonization and phagocytosis completely. Digests of crosslinked fibrin clot also inhibited opsonization, although slightly less effectively than did fibrinogen digests. The antiopsonic effect of fibrin(ogen) degradation products may be relevant to circumstances in which fibrin(ogen)olysis is occurring, e.g., exudation and suppuration.

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Inhibition of complement-mediated opsonization and phagocytosis of Streptococcus pyogenes by D fragments of fibrinogen and fibrin bound to cell surface M protein.

We have isolated an intermediate plasmic degradation product, D2, of fibrinogen that does not inhibit the polymerization of fibrin monomer but does bind Ca2+. Fibrinogen was digested to a limited extent with plasmin in the presence of Ca2+, and a "large" fragment D (fragment D1A) was isolated with a gamma-chain remnant consisting of residues 63-411. Fragment D1A was digested further in the presence of Ca2+, yielding fragment D1 (with its gamma-chain containing residues 86-411). The digestion of fragment D1 [in the presence of ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) to complex Ca2+] led to a gradual shortening of the carboxyl-terminal portion of the gamma-chain. Fragment D2 (with its gamma-chain containing residues 86-335/356) was isolated from an intermediate digest in the presence of EGTA. The Lys-338-Cys-339 peptide bond of the gamma-chain is intact in this preparation of D2, even though it is split in the isolated peptide gamma303-355 (with an intact disulfide bond at Cys-326-Cys-339). Fragment D2 does not interfere with the polymerization of fibrin monomer, whereas fragment D1 is a potent inhibitor of this polymerization. We conclude that the gamma-chain segment 356/357-411, present in fragment D1 but absent from fragment D2, is essential for maintenance of a polymerization site located in the outer (D) nodule of fibrinogen. This segment (356/357-411) is longer than two shorter ones reported earlier [Olexa, S.A., & Budzynski, A. Z. (1981) J. Biol. Chem. 256, 3544-3549; Horwitz, B.H., Varadi, A., & Scheraga, H.A. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 5980-5984]; the data for the earlier reports are reinterpreted here. Finally, fragment D2 possesses a single Ca2+ binding site, as revealed by equilibrium dialysis binding studies. Since fragment D3 (with its gamma-chain containing residues 86-302) fails to bind Ca2+, we conclude that segment gamma 303-355/356 plays a crucial role in Ca2+ binding.

Localization of segments essential for polymerization and for calcium binding in the gamma-chain of human fibrinogen.

Publisher Summary This chapter highlights fibrinogen, fibrin, and factor XIII. Fibrinogen is a blood plasma protein, which induced by the action of the enzyme thrombin is converted into an insoluble gel or clot, called “fibrin.” Fibrinogen exists in free form in the blood, but thrombin is normally present as its inactive precursor prothrombin. Blood plasma fibrinogen is synthesized in the parenchymal cells of the liver. Fibrinogen occurs, however, also in the platelets, and this form of the protein seems to be synthesized in the megakaryocytes of the bone marrow. The most important biological function of fibrinogen is to clot and thereby form a barrier against blood leakage through a damaged blood vessel wall, the fibrin clot acting as a network retaining blood cells and certain plasma proteins. The fibrin framework is also believed to support fibroblast proliferation during wound healing. The fibrinogen assay methods are in most cases based upon one of the determination principles—namely, coagulation time or velocity, and amount of coagulable protein or specifically precipitable protein or specifically immunoreactive protein.

Chapter 7 Fibrinogen, fibrin and factor XIII

Fibrinogen is a thrombin-coagulable glycoprotein occurring in the blood of vertebrates. The primary structure of the alpha, beta, and gamma polypeptide chains of human fibrinogen is known from amino acid and nucleic acid sequencing. The intact molecule has a trinodular, dimeric structure and is functionally bivalent. Thrombin cleaves short peptides from the amino termini of the alpha and beta chains exposing polymerization sites that are responsible for the formation of fibrin fibers and appearance of a clot. The major physiological function of fibrinogen is the formation of fibrin that binds together platelets and some plasma proteins in a hemostatic plug. In pathological situations, the network entraps large numbers of erythrocytes and leukocytes forming a thrombus that may occlude a blood vessel. Fibrinogen and fibrin are multifunctional proteins. Fibrinogen is indispensable for platelet aggregation; it also binds to several plasma proteins, however, the biological function of this interaction is not completely understood. Fibrin is an essential matrix for regulation of fibrinolysis and for facilitation of cell attachment in wound healing.

Fibrinogen and fibrin: biochemistry and pathophysiology.

Substitution of gamma Arg-275 by Cys in an abnormal fibrinogen, "fibrinogen Osaka II". Evidence for a unique solitary cystine structure at the mutation site.

Fibrinogen fragment D1 was converted to fragment D3 by plasmic digestion. This conversion eliminates the ability of the fragment to interact with thrombin-exposed sites on fibrin monomer. Peptides released during this plasmic digestion were assayed for the presence of a polymerization site by affinity chromatography on fibrin monomer-Sepharose. We found that a 33-residue peptide, corresponding to gamma-chain Thr-374 to Lys-406, binds to immobilized fibrin monomer. This peptide is a shorter variant of a previously isolated 38-residue peptide (gamma-chain Thr-374 to Val-411) that contains a polymerization site [Olexa, S. A. & Budzynski, A. Z. (1981) J. Biol. Chem. 256, 3544-3549]. The peptide mixture derived from fragment D1 was digested further with Staphylococcus aureus protease V8, and a 23-residue peptide, gamma-chain Thr-374 to Glu-396, carrying a polymerization site, was isolated by affinity chromatography. This 23-residue peptide inhibits the polymerization of desA-fibrinogen. We conclude that a polymerization site complementary to the site exposed by removal of fibrinopeptide A is present in this segment. The localization of the polymerization site within the gamma-chain segment 374-396 implies that the polymerization site does not overlap with segments of the gamma-chain that are responsible for platelet aggregation and for Staphylococcus clumping (residues 400-411 and 397-411, respectively) or with the residues involved in factor XIIIa-catalyzed fibrin crosslinking (Gln-398 and Lys-406).

Localization of a fibrin gamma-chain polymerization site within segment Thr-374 to Glu-396 of human fibrinogen.

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Localization of a fibrin gamma-chain polymerization site within segment Thr-374 to Glu-396 of human fibrinogen.