7kxy
From Proteopedia
Cryo-EM structure of human Factor Va at 4.4 Angstrom resolution
Structural highlights
DiseaseFA5_HUMAN Defects in F5 are the cause of factor V deficiency (FA5D) [MIM:227400; also known as Owren parahemophilia. It is a hemorrhagic diastesis.[1] [2] Defects in F5 are the cause of thrombophilia due to activated protein C resistance (THPH2) [MIM:188055. THPH2 is a hemostatic disorder due to defective degradation of factor Va by activated protein C. It is characterized by a poor anticoagulant response to activated protein C resulting in tendency to thrombosis.[3] [4] [5] [6] [7] Defects in F5 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:600880. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. Defects in F5 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:601367; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.[8] Defects in F5 are associated with susceptibility to pregnancy loss, recurrent, type 1 (RPRGL1) [MIM:614389. RPRGL1 is a common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.[9] FunctionFA5_HUMAN Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin. Publication Abstract from PubMedCoagulation factor V is the precursor of factor Va that, together with factor Xa, Ca2+ and phospholipids, defines the prothrombinase complex and activates prothrombin in the penultimate step of the coagulation cascade. Here we present cryo-EM structures of human factors V and Va at atomic (3.3 A) and near-atomic (4.4 A) resolution, respectively. The structure of fV reveals the entire A1-A2-B-A3-C1-C2 assembly but with a surprisingly disordered B domain. The C1 and C2 domains provide a platform for interaction with phospholipid membranes and support the A1 and A3 domains, with the A2 domain sitting on top of them. The B domain is highly dynamic and visible only for short segments connecting to the A2 and A3 domains. The A2 domain reveals all sites of proteolytic processing by thrombin and activated protein C, a partially buried epitope for binding factor Xa and fully exposed epitopes for binding activated protein C and prothrombin. Removal of the B domain and activation to fVa exposes the sites of cleavage by activated protein C at R306 and R506 and produces increased disorder in the A1-A2-A3-C1-C2 assembly, especially in the C-terminal acidic portion of the A2 domain responsible for prothrombin binding. Ordering of this region and full exposure of the factor Xa epitope emerge as a necessary step for the assembly of the prothrombin-prothrombinase complex. These structures offer molecular context for the function of factors V and Va and pioneer the analysis of coagulation factors by cryo-EM. Cryo-EM structures of human coagulation factors V and Va.,Ruben EA, Rau MJ, Fitzpatrick J, Di Cera E Blood. 2021 Mar 8. pii: 475464. doi: 10.1182/blood.2021010684. PMID:33684942[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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