Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders

Kane, WH; Davie, EW

doi:10.1182/blood.v71.3.539.bloodjournal713539

Cited by 45 publications

(49 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…the 27 C-terminal rcsidues in thc A2 domain. Ten times more of this factor Va was required for half-miixitnal incorporation of flictor Xa into the membrme-hound Factor-Xafactor-% complcx compared with full-length factor Va. Based on the homology between factor V and factor VIIT (Kane and Davie, 1988) and the ftinctional similarities between the factor-Va-factor-Xa and the factor VIIla-factor-lXa complexes, this may infcr an impaircd incorporation of factor IXa into the nieinbranc-bound complex with FVIll-( 1 -720). This could be an additional explanation for the lower specific clotting activity of The influence of tyrosine sulfation on factor VIII activity has bcen the subject of earlier studies.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Residues 721–729 are Required for Full Factor VIII Activity

Kjalke

Heding

Talbo

et al. 1995

European Journal of Biochemistry

View full text Add to dashboard Cite

Recombinant two-chain fiictor VIII, from which the B domain had bccn deleted, wiis cxpressetl in Chinese hamster ovary cells. In addition to the major product. three minor factor VIIl forms were isolated. The A2 domains generated by thrombin clcavage showed dillcrcnt eleclrophoretic inohilities. Peptidc mapping of the A2 domains showed that two of the faclor V l l l forms had the expected C-terminus (of the heavy chain at Arg740 IFVIII-( 1 -740)] and that the other faclor V l l l forms hxi ('-termini at Tyr729 [FV111-(1-729)1 or Glu720 [FVIII-(I -720)l. The major FVIII-(1-740) form, FVTII-(1 -729)> and FV111-(1-720) contained sulfated tyrosine residues iit Tyr7 18, Tyr7 I9 and 'Iyr723. The minor FVIII-( 1 -740) form was shown to lack sulfation at these positions. The spccific clotting activity was apprcsxiinatcly 1 X 104 U/mg for FVIII-( 1-740) (both forms) and FVIII-( 1 -729), hut twofold lower for FVIII-( 1-720). A time study of thrombin activation showed that FVIIT-(1-720) was activated slowcr than FVIII-( 1 -740), FVIII-(I -729) and pliisma-derived factor VIII. Partinlly sulfiltcd FVIII-(l -740) was activated at the same rate as the fully sulfated FVIII-(I -740). The cquilibi~ium dissociation conslant for binding of factor VlII to inactivated immobilized thrombin was the satrie lor all factor Vlll forms, showing that the slower activation of FVIII-( 1-720) was not due to a lower affinity for the anion-hinding cxosite in thrombin.Kqywords: coagulation factor VIII; tyrosine sulfate; thrombin ; surface plastnon resonance; niatrix-assisted-laser-desorption/ionization MS.Coagulation factor VTTI circulates in plasma as a procofactor ociatetl with von Willebrand factor. After activation by factor Xa o r thrombin, factor VIlla dissociates from von Willebrand factor arid is integrated inlo ii calciun-dependent complex with factor IXa on cellular surfaces or, in virm, on phospholipid vesicles. In the complex, factor VllIa functions as a cofactor for fiictor-IX~i-rnrdiated activation of factor X, which in turn activates thrombin, thereby enhancing the activation of the clotting cascade.Factor VIII has the domain structure A 1 -A2-B-A3-C I -C2 (Vehar et al., 1984; Toole el al., 1984). Factor VIII is isolatcd from plasma as a series of heterodimers consisting of a heavy chain (the A I -A2-B domains) of 90-200 kDa, and a light chain (A3-Cl-C2) of 80 kDa (Vehar ei al., 19x4; Aiidersson et al., 1986) held togethcr by a divalent cation (Fass e l al., 1982; Trueii et al., 1985). When factor VIIl i s activated by thrombin, a 41-amino-acid peptide is liberated fro111 the N-terminus of the light chain by cleavage at Argl689 ant1 rcrrioval o f thc B domain is completed by cleavage al Arg740 followcd by cleavage of the heavy chiiin belwccn the A1 and A2 domains at Arg372 (Euton ct al., 19x6: Fay et ul., 1986). This results in the formation 01

show abstract

Section: Discussionmentioning

confidence: 99%

Amino Acid Residues 721–729 are Required for Full Factor VIII Activity

Kjalke

Heding

Talbo

et al. 1995

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…1). During blood coagulation, the DS domains of factor V and VIII are thought to bind to phospholipids at the surface of platelets (30). The threedimensional structure of the DS domains of factor V has been recently predicted using the homologous structure of galactose oxidase (31).…”

Section: Ddr-related Proteinsmentioning

confidence: 99%

Discoidin domain receptors: structural relations and functional implications

1999

View full text Add to dashboard Cite

Multicellular life relies on the presence of extracellular matrix to provide scaffolding for cells and tissue compartments. To provide communication between cells and tissues, a multitude of cell surface receptors are triggered by soluble ligands and components of the extracellular matrix. A large family of these receptors transmit signals through the use of an intrinsic tyrosine kinase function. The subgroup of discoidin domain receptors (DDRs) is distinguished from other members of the receptor tyrosine kinase family by a discoidin homology repeat in their extracellular domains that is also found in a variety of other transmembrane and secreted proteins. Sequence comparisons show that non-mammalian orthologs of DDRs exist: three closely related genes in Caenorhabditis and one in the sponge Geodia cydonium. Recently, various types of collagen have been identified as the ligands for the two mammalian discoidin domain receptor tyrosine kinases, DDR1 and DDR2. The binding of collagen to DDRs results in a delayed but sustained tyrosine kinase activation. Both receptors display several potential tyrosine phosphorylation sites that are able to relay the signal by interacting with cytoplasmic effector proteins. The potential cross-talk to other receptors for collagen and the clinical aspects of DDR function are discussed.

show abstract

“…For example, in the final step of blood clot formation, thrombin converts soluble fibrinogen into fibrin and subsequently triggers cross-linking between fibrin monomers by activating factor XIII [1]. It also amplifies its own generation by activating nonenzymatic cofactors V and VIII as well as factor XI [2,3]. Conversely, it suppresses its own generation by activating protein C [4], which inactivates factor Va and factor VIIIa together with protein S [5], when bound to the endothelial membrane receptor thrombomodulin.…”

mentioning

confidence: 99%

Identification and characterization of novel salivary thrombin inhibitors from the ixodidae tick, Haemaphysalis longicornis

et al. 2003

View full text Add to dashboard Cite

Novel antithrombin molecules were identified from the ixodidae tick, Haemaphysalis longicornis. These molecules, named madanin 1 and 2, are 7-kDa proteins and show no significant similarities to any previously identified proteins. Assays using human plasma showed that madanin 1 and 2 dose-dependently prolonged both activated partial thromboplastin time and prothrombin time, indicating that they inhibit both the intrinsic and extrinsic pathways. Direct binding assay by surface plasmon resonance measurement demonstrated that madanin 1 and 2 specifically interacted with thrombin. Furthermore, it was clearly shown that madanin 1 and 2 inhibited conversion of fibrinogen into fibrin by thrombin, thrombin-catalyzed activation of factor V and factor VIII, and thrombin-induced aggregation of platelets without affecting thrombin amidolytic activity. These results suggest that madanin 1 and 2 bind to the anionbinding exosite 1 on the thrombin molecule, but not to the active cleft, and interfere with the association of fibrinogen, factor V, factor VIII and thrombin receptor on platelets with an anion-binding exosite 1. They appear to be exosite 1-directed competitive inhibitors.Keywords: anticoagulant; Haemaphysalis longicornis; salivary gland; thrombin inhibitor; tick.Thrombin has various physiological functions and plays important roles in hemostasis. For example, in the final step of blood clot formation, thrombin converts soluble fibrinogen into fibrin and subsequently triggers cross-linking between fibrin monomers by activating factor XIII [1]. It also amplifies its own generation by activating nonenzymatic cofactors V and VIII as well as factor XI [2,3]. Conversely, it suppresses its own generation by activating protein C [4], which inactivates factor Va and factor VIIIa together with protein S [5], when bound to the endothelial membrane receptor thrombomodulin. In addition, thrombin induces platelet aggregation via proteolytic activation of G-protein-coupled protease-activated receptors (PARs) [6,7]. Specific interactions of thrombin with these substrates, cofactors, and receptors involve not only the catalytic site and the primary binding pocket, but also secondary recognition sites, termed anion-binding exosite 1 and 2. Anion-binding exosite 1 interacts with negatively charged domains on fibrinogen [8], PARs [6,7,9], and thrombomodulin [10,11]. Anion-binding exosite 2 interacts with heparin [12], promoting inhibition of thrombin by antithrombin III [13] and heparin cofactor II [14]. Furthermore, both exosites are involved in the recognition of factor V and factor VIII by thrombin [15].The salivary glands of blood-sucking animals, such as leeches, insects, and ticks, contain various anticoagulants [16]. These substances inhibit the host hemostatic response so that the blood-sucking organism can feed smoothly on host blood. The best known anticoagulant identified from bloodsucking organisms is hirudin, a highly specific thrombin inhibitor, isolated from the medical leech, Hirudo medicinalis [17]. It interacts with tw...

show abstract

Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders

Cited by 45 publications

References 0 publications

Amino Acid Residues 721–729 are Required for Full Factor VIII Activity

Amino Acid Residues 721–729 are Required for Full Factor VIII Activity

Discoidin domain receptors: structural relations and functional implications

Identification and characterization of novel salivary thrombin inhibitors from the ixodidae tick, Haemaphysalis longicornis

Contact Info

Product

Resources

About