Mutating factor VIII: lessons from structure to function.

Philip J Fay; P Vincent Jenkins

doi:10.1016/j.blre.2004.02.003

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Mutating factor VIII: lessons from structure to function.

Philip J Fay·P Vincent Jenkins

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Abstract

Factor VIII, a metal ion-dependent heterodimer, circulates in complex with von Willebrand factor. At sites of vessel wall damage, this procofactor is activated to factor VIIIa by limited proteolysis and assembles onto an anionic phospholipid surface in complex with factor IXa to form the intrinsic factor Xase; an enzyme complex that efficiently converts factor X to factor Xa during the propagation phase of coagulation. Factor Xase activity is down-regulated by mechanisms that include self-dampening by dissociation of a critical factor VIIIa subunit and proteolytic inactivation by the activated protein C pathway. Recent studies identify putative metal ion coordination sites as well as ligands involved in the catabolism of the activated and procofactor forms of the protein. Our knowledge of these multiple intra- and inter-molecular interactions has been facilitated by the application of naturally occurring and site-directed mutations to study factor VIII structure and function. In this review, we document important and novel contributions following this line of investigation.

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Cysteine Endopeptidases Factor VIII Factor VIIIa Hemophilia A Humans Models, Molecular Mutagenesis, Site-Directed Mutation Neoplasm Proteins Protein Conformation Protein Structure, Tertiary Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.Review

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Philip J Fay, P Vincent Jenkins. 2005. Mutating factor VIII: lessons from structure to function.. https://doi.org/10.1016/j.blre.2004.02.003

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