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.v71.3.539.539

Cited by 402 publications

(174 citation statements)

References 49 publications

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“…Like non‐missense mutations, missense alterations are often reported to induce a severe phenotype, mainly if they modify protein locations that are conserved: (1) in the FVIII of different species (Kane et al , 1988; Pratt et al , 1999); (2) in proteins that present an analogous structure, such as human Cp (Koschinsky et al , 1986), FV (Jenny et al , 1987; Yang et al , 1998), He and Ha. The novel missense mutations that we found (Table II, Fig 2), were located in both the heavy (A1–A2 domains) and the light chains (A3–C1–C2 domains), and they affected residues that were conserved at least in the FVIII protein of all the examined species.…”

Section: Missense Mutationsmentioning

confidence: 99%

“…The native protein is a multidomain protein containing three A‐type domains, one B domain and two C‐type domains. The A domains, each sharing ∼ 30% sequence identity among themselves, are homologous to the triplicate A domains present in human ceruloplasmin (hCp) and factor V (FV) (Church et al , 1984; Kane & Davie, 1988). By investigating (http://usexpasy.org) the overall percentage of homology with several other proteins (data not shown), we found that human, rat and murine hephaestin (He) (Vulpe et al , 1999; Frazer et al , 2001; Syed et al , 2002) and murine haphaestin (Ha) (NCBI, protein XP_146812) share a similar percentage of identity with the human FVIII A domains.…”

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confidence: 99%

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Analysis of 18 novel mutations in the factor VIII gene

Bicocchi¹,

Pasino²,

Lanza³

et al. 2003

Br J Haematol

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Summary. We describe 18 novel mutations, unreported in the Haemophilia A mutation Databases, that have been identified in a cohort of unrelated, Italian patients affected with haemophilia A (HA). Screening of the factor VIII gene (FVIII) was performed using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing. Eight mutations were characterized as non-missense alterations, and the remaining 10 were missense mutations. Heterozygosity for the identified mutations was observed in the female relatives of patients belonging to eight families with sporadic cases. In an attempt to understand better the causative effect of the mutations and the clinical variability of the patients, missense mutation consequences were investigated for: (1) the nature of the new amino acid; (2) the location of the substituted amino acid within crystallographic and theoretical models; and (3) the degree of conservation of the native residue in factor VIII (FVIII) protein and FVIII-related protein family aligned sequences. These research tools have provided evidence that the mutations we describe involve residues that were conserved, at least in FVIII proteins, in all the species we compared.

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Section: Missense Mutationsmentioning

confidence: 99%

mentioning

confidence: 99%

Analysis of 18 novel mutations in the factor VIII gene

Bicocchi¹,

Pasino²,

Lanza³

et al. 2003

Br J Haematol

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“…Factor VIII (FVIII) is a large plasma glycoprotein of 2332 amino acid residues organized in six domains: A1–A2–B–A3–C1–C2 . The three A (3A) domains are homologous to each other, to the A domains of Factor V (FV), and the copper‐binding protein ceruloplasmin .…”

Section: Introductionmentioning

confidence: 99%

Domain organization of membrane‐bound factor VIII

et al. 2013

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Factor VIII (FVIII) is the blood coagulation protein which when defective or deficient causes for hemophilia A, a severe hereditary bleeding disorder. Activated FVIII (FVIIIa) is the cofactor to the serine protease factor IXa (FIXa) within the membrane-bound Tenase complex, responsible for amplifying its proteolytic activity more than 100,000 times, necessary for normal clot formation. FVIII is composed of two noncovalently linked peptide chains: a light chain (LC) holding the membrane interaction sites and a heavy chain (HC) holding the main FIXa interaction sites. The interplay between the light and heavy chains (HCs) in the membrane-bound state is critical for the biological efficiency of FVIII. Here, we present our cryo-electron microscopy (EM) and structure analysis studies of human FVIII-LC, when helically assembled onto negatively charged single lipid bilayer nanotubes. The resolved FVIII-LC membrane-bound structure supports aspects of our previously proposed FVIII structure from membrane-bound two-dimensional (2D) crystals, such as only the C2 domain interacts directly with the membrane. The LC is oriented differently in the FVIII membrane-bound helical and 2D crystal structures based on EM data, and the existing X-ray structures. This flexibility of the FVIII-LC domain organization in different states is discussed in the light of the FVIIIa-FIXa complex assembly and function.

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“…The relative contribution of plasma and platelet factor V to hemostasis in humans is uncertain, although platelet factor V can support hemostasis in individuals with plasma factor V deficiency (1,4,(6)(7)(8). Factor V is encoded by a single copy gene (1,9) and compared to plasma factor V, human platelet factor V has a more heterogeneous reduced size (due to partial activation and proteolysis within the B-domain) and it is also more resistant to Thromb Haemost 2004; 92: 1349-57 iable size and included forms larger than factor V dimers, the data suggested disulfide-linkage with another platelet protein, possibly multimerin. Immunoprecipitation experiments confirmed that unusually large factor V was associated with multimerin and it remained associated in 0.5 M salt.…”

Section: Introductionmentioning

confidence: 99%

“…

IntroductionFactor V is an important coagulation cofactor that accelerates the conversion of prothrombin to thrombin after conversion to factor Va (1, 2). In humans and animals, congenital factor V deficiency results in bleeding and a partial to complete loss of the factor V that circulates in plasma and in platelets (1, 3-5).The relative contribution of plasma and platelet factor V to hemostasis in humans is uncertain, although platelet factor V can support hemostasis in individuals with plasma factor V deficiency (1,4,(6)(7)(8). Factor V is encoded by a single copy gene (1,9) and compared to plasma factor V, human platelet factor V has a more heterogeneous reduced size (due to partial activation and proteolysis within the B-domain) and it is also more resistant to Thromb Haemost 2004; 92: 1349-57 iable size and included forms larger than factor V dimers, the data suggested disulfide-linkage with another platelet protein, possibly multimerin.

…”

mentioning

confidence: 99%

Human platelets contain forms of factor V in disulfide-linkage with multimerin

et al. 2004

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Factor V is an essential cofactor for blood coagulation that circulates in platelets and plasma. Unlike plasma factor V, platelet factor V is stored complexed with the polymeric alpha-granule protein multimerin. In analyses of human platelet factor V on nonreduced denaturing multimer gels, we identified that approximately 25% was variable in size and migrated larger than single chain factor V, the largest form in plasma. Upon reduction, the unusually large, variably-sized forms of platelet factor V liberated components that comigrated with other forms of platelet factor V, indicating that they contained factor V in interchain disulfide-linkages. With thrombin cleavage, factor Va heavy and light chain domains, but not B-domains,were liberated from the components linked by interchain disulfide bonds, indicating that the single cysteine in the B-domain at position 1085 was the site of disulfide linkage. Since unusually large factor V had a variable size and included forms larger than factor V dimers, the data suggested disulfide-linkage with another platelet protein, possibly multimerin. Immunoprecipitation experiments confirmed that unusually large factor V was associated with multimerin and it remained associated in 0.5 M salt. Moreover, platelets contained a subpopulation of multimerin polymers that resisted dissociation from factor V by denaturing detergent and comigrated with unusually large platelet factor V, before and after thrombin cleavage. The disulfide-linked complexes of multimerin and factor V in platelets, which are cleaved by thrombin to liberate factor Va, could be important for modulating the function of platelet factor V and its delivery onto activated platelets. Factor Va generation and function from unusually large platelet factor V is only speculative at this time.

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

Cited by 402 publications

References 49 publications

Analysis of 18 novel mutations in the factor VIII gene

Analysis of 18 novel mutations in the factor VIII gene

Domain organization of membrane‐bound factor VIII

Human platelets contain forms of factor V in disulfide-linkage with multimerin

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