title: Inhibitory sequences within the B-domain stabilize circulating factor V in an inactive state.
abstract: Blood coagulation factor V circulates as a procofactor with little or no procoagulant activity. It is activated to factor Va by thrombin following proteolytic removal of a large central B-domain. Although this reaction is well studied, the mechanism by which bond cleavage and B-domain release facilitate the transition to the active cofactor state has not been defined. Here we show that deletion or substitution of specific B-domain sequences drives the expression of procoagulant function without the need for proteolytic processing. Conversion to the constitutively active cofactor state is related, at least in part, to a cluster of amino acids that is highly basic and well conserved across the vertebrate lineage. Our findings demonstrate that discrete sequences in the B-domain serve to stabilize the inactive procofactor state, with proteolysis primarily functioning to remove these inhibitory constraints. These unexpected results provide new insight into the mechanism of factor V activation.
authors: Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors: Hua
authors: H
authors: Zhu
authors: Raffaella
authors: R
authors: Toso
authors: Rodney M
authors: RM
authors: Camire
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution; D003067:Coenzymes / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D005165:Factor V / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D003067:Coenzymes; D005165:Factor V