Proteolytic Processing of Von Willebrand Factor by Adamts13 and Leukocyte Proteases

Abstract

ADAMTS13 is a 190 kDa zinc protease encoded by a gene located on chromosome 9q34. This protease specifically hydrolyzes von Willebrand factor (VWF) multimers, thus causing VWF size reduction. ADAMTS13 belongs to the A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS) family, involved in proteolytic processing of many matrix proteins. ADAMTS13 consists of numerous domains including a metalloprotease domain, a disintegrin domain, several thrombospondin type 1 (TSP1) repeats, a cysteine-rich domain, a spacer domain and 2 CUB (Complement c1r/c1s, sea Urchin epidermal growth factor, and Bone morphogenetic protein) domains. ADAMTS13 cleaves a single peptide bond (Tyr1605-Met1606) in the central A2 domain of the VWF molecule. This proteolytic cleavage is essential to reduce the size of ultra-large VWF polymers, which, when exposed to high shear stress in the microcirculation, are prone to form with platelets clumps, which cause severe syndromes called thrombotic microangiopathies (TMAs). In this review, we a) discuss the current knowledge of structure-function aspects of ADAMTS13 and its involvement in the pathogenesis of TMAs, b) address the recent findings concerning proteolytic processing of VWF multimers by different proteases, such as the leukocyte-derived serine and metallo-proteases and c) indicate the direction of future investigations.

The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

“…Inherited TTP is a rare autosomal recessive disorder due to homozygous or double heterozygous mutations in the ADAMTS-13 gene, causing a severe decrease of ADAMTS-13 level and activity (10)(11)(12)(13)(14)(15)(16). About 100 mutations causing inherited ADAMTS-13 deficiency have been identified so far in regions of the gene encoding different domains (10)(11)(12)(13)(14)(15)(16)(17) with only a few of them characterized by in vitro expression studies (12,15,(18)(19)(20)(21)(22). In this manuscript, we report cases of congenital TTP, due to the homozygous mutation in ADAMTS-13 gene in two young brothers born from two consanguineous parents of Romanian origin.…”

Solving the Measurement Problem and then Steppin’ Out over the Line Riding the Rarest Italian: Crossing the Streams to Retrieve Stable Bioactivity in Majorana Bound States of Dialy zed Human Platelet Lysates

“…ADAMTS13 is a metalloprotease that mediates cleavage of vwF, with a recognized role in syndromes of thromobotic microangiopathy resulting from aberrant polymerization of vwF, and consequent clumping of platelets at sites of high shear stress in the vasculature [ 67 ]. This factor contains two “CUB” domains, a motif named for the presence of sequences sharing homology with complement elements C1r/C1s, a sea urchin protein, Uegf, and BMP-1 [ 67 ], a protease of the astacin family. Multiple cysteine residues within each of these two domains are required for stability and secretion of ADAMTS13 [ 68 ].…”

“…The role of CUB domains in orientation is further suggested by similarities in the interaction of Neuropilin-1 (NRP-1) with Sema3a and plexin that regulates axonal guidance through cytoskeletal influences [ 74 ], and the vwF interaction with FVIII critical to regulation of platelet aggregation [ 67 ]. The presence of two CUB domains and two FactorV/FactorVIII-like discoidin domains in NRP-1 suggests it may have a role comparable to ADAMTS13 in the vwF axis.…”

ADAMTS13 and von Willebrand factor interactions

“…The ADAMTS family proteases are zinc-containing metalloproteases [41–43] that, unlike ADAM family proteases, are not membrane bound due to the lack of a membrane-anchor domain [44,45]. ADAMTS13, similar to other ADAMTS proteases, is comprised of a metalloprotease domain, a disintegrin-like domain, the first thrombospondin type 1 repeat, a cysteine-rich domain, and a spacer domain (Fig.…”

“…This catalytic site is further characterized by a conserved downstream methionine residue. This ‘Metturn’ creates a tight turn, important to the structure of the active site, which possibly acts as a hydrophobic base beneath the zinc ion [44,55]. Between this conserved methionine and catalytic site, there is also a well conserved cysteine residue of unknown function [45,46].…”