1de7
From Proteopedia
INTERACTION OF FACTOR XIII ACTIVATION PEPTIDE WITH ALPHA-THROMBIN: CRYSTAL STRUCTURE OF THE ENZYME-SUBSTRATE COMPLEX
Structural highlights
Disease[THRB_HUMAN] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:613679]. It is a very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Genetic variations in F2 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.[13] Defects in F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM:188050]. It is a multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Defects in F2 are associated with susceptibility to pregnancy loss, recurrent, type 2 (RPRGL2) [MIM:614390]. 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.[14] Function[THRB_HUMAN] Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.[15] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe serine protease thrombin proteolytically activates blood coagulation factor XIII by cleavage at residue Arg(37); factor XIII in turn cross-links fibrin molecules and gives mechanical stability to the blood clot. The 2.0-A resolution x-ray crystal structure of human alpha-thrombin bound to the factor XIII-(28-37) decapeptide has been determined. This structure reveals the detailed atomic level interactions between the factor XIII activation peptide and thrombin and provides the first high resolution view of this functionally important part of the factor XIII molecule. A comparison of this structure with the crystal structure of fibrinopeptide A complexed with thrombin highlights several important determinants of thrombin substrate interaction. First, the P1 and P2 residues must be compatible with the geometry and chemistry of the S1 and S2 specificity sites in thrombin. Second, a glycine in the P5 position is necessary for the conserved substrate conformation seen in both factor XIII-(28-37) and fibrinopeptide A. Finally, the hydrophobic residues, which occupy the aryl binding site of thrombin determine the substrate conformation further away from the catalytic residues. In the case of factor XIII-(28-37), the aryl binding site is shared by hydrophobic residues P4 (Val(34)) and P9 (Val(29)). A bulkier residue in either of these sites may alter the substrate peptide conformation. Interaction of the factor XIII activation peptide with alpha -thrombin. Crystal structure of its enzyme-substrate analog complex.,Sadasivan C, Yee VC J Biol Chem. 2000 Nov 24;275(47):36942-8. PMID:10956659[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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