User:Cynthia Pruss/Sandbox 1
From Proteopedia
VWF A2 domain
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Von Willebrand factor (VWF) is a large multimeric glycoprotein with a critical role in maintaining hemostasis. VWF serves as the carrier protein for the plasma coagulation protein factor VIII (FVIII) and promotes platelet adhesion and aggregation at the sites of vascular damage (2,3). The hemostatic potential of VWF greatly increases with the multimer size, which is tightly regulated in vivo by the metalloprotease ADAMTS13.
ADAMTS13 is the thirteenth member of the A disintegrin-like and metalloprotease with thrombospondin type 1 motif family of proteases. ADAMTS13 cleaves VWF between Tyr1605-Met1606, and maintains plasma VWF within a normal molecular weight range by cleaving high molecular weight (HMW) multimers soon after they are secreted into the plasma, preventing spontaneous platelet agglutination.
The A2 domain is not stabilized by disulfide bonds within VWF, unlike A1 and A3. In addition, the A2 domain lacks the highly conserved α4 helix, which has been replaced with the flexible and dynamic α4-less loop.Template:706 This leads to low resistance to unfolding, giving the A2 domain the function of a shear bolt. A shear bolt breaks above a designed force threshold, to protect other parts of a machine from accidental damage. Similarly, the A2 domain unfolds when present in VWF multimers that experience high tensile force and is cleaved by ADAMTS13, resulting in down regulation of the hemostatic activity.Template:705 VWF will only be exposed to peak shear forces intermittently in the arterioles in normal circulation, but when tethered, VWF will undergo longer, higher shear rates, causing the A2 domain to unfold and allowing ADAMTS13 access to the A2 domain’s central cleavage site.Template:706 These shear forces will increase at sites of vascular damage with a growing thrombus that narrows vessel diameter. ADAMTS13 serves to halt the growth of the thrombus to prevent vessel occlusion, as has been demonstrated in vitro.Template:668 The minimal substrate for ADAMTS13 cleavage is the A2 domain’s D1596-R1668, VWF73.Template:133 Several exosites in ADAMTS13 interact with the VWF A2 domain to contribute to substrate specificity and enhance cleavage efficiency. First, the first TSP1 spacer domain in ADAMTS13 interacts with VWF residues between Gln1624 and Arg1668, increasing the cleavage rate 300-fold.Template:690 The exosite binding was further refined to identify three additional exosites, the first involving VWF1596-1623, the second VWF1642-1652, and the third VWF1653-1668, that are exposed when the VWF A2 domain is unfolded.Template:694
Type 2A group II von Willebrand disease mutations have increased susceptability to ADAMTS13-mediated proteolysis. These are located in the A2 domain. These include R1597W.
The A2 domain has several naturally occuring single nucleotide polymorphisms that alter the amino acid sequence. These include Q/H1571, P/T1601, I/T1628 and G/S1643 (2).
References:
1. Zhang Q, Zhou YF, Zhang CZ, Zhang X, Lu C, Springer TA. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor. Proc Natl Acad Sci U S A. 2009;106:9226-9231.
2. http://www.vwf.group.shef.ac.uk/ The International Society for Thrombosis and Haemostasis (ISTH)-SSC VWF Online Database has a listing of known mutations and polymorphisms.
