N-terminal of ADAMTS13 essential for arterial thrombosis inhibition
MedWire News: The amino terminus of the metalloprotease ADAMTS13 has a crucial role in the modulation of arterial thromboses, study findings indicate.
ADAMTS13, a member of the "a disintegrin-like and metalloprotease with thrombospondin type 1 repeats" family of proteins, inhibits platelet aggregation and arterial thrombosis by cleavage of von Willebrand factor, explain X Long Zheng (Children's Hospital of Philadelphia, Pennsylvania, USA) and co-researchers.
However, the structural components of ADAMTS13 required for inhibition of arterial thrombosis are not fully defined, they add.
To address this, Zheng and team treated ADAMTS13 knockout (ADAMTS13-/-) mice with recombinant ADAMTS13, truncated at various positions throughout the protein, in a murine model of thrombosis.
ADAMTS13 consists of a metalloprotease domain, a disintegrin domain, the first thrombospondin type 1 (TSP1) repeat, a Cys-rich domain, and spacer (S) domains. The more distal C terminus has seven additional TSP1 repeats.
The researchers demonstrated that an ADAMTS13 variant truncated after either the eighth TSP1 (TS8) repeat or the S domain inhibited ferric chloride-induced arterial thrombosis in ADAMTS13-/- mice with similar efficacy to that of full-length (FL) ADAMTS13.
Specifically, the mean time to the complete vessel occlusion following injury in the carotid artery of ADAMTS13-/- mice (C57BL/6) was 5.4 minutes (n=14), which was significantly shorter than the 10.4 minutes observed in wild-type mice.
Infusion of recombinant FL, T8, and S ADAMTS13 (6-10 nmol/l) immediately before ferric chloride injury increased the occlusion time in ADAMTS13-/- mice to 13.4 (n=16), 11.1 (n=15), and 20.0 minutes (n=16), respectively.
"These results suggest that the amino-terminal half of ADAMTS13 (up to the spacer domain) is sufficient for inhibition of arterial thrombosis," remark Zheng and co-authors in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.
Similar results were observed when researchers tested the effect of the ADAMTS13 variants on thrombus formation in mesenteric arterioles, which the researchers say confirms that the amino-terminus of ADAMTS13 is required for inhibition of arterial thrombosis.
They conclude: "These findings shed more light on the structure-function relationship of ADAMTS13 in vivo and may be applicable for rational design of protein- or gene-based therapy of arterial thromboses."
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By Laura Dean