Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura is associated with acquired or congenit al deficiency of a plasma von Willebrand factor-cleaving protease (VWFCP). Based on partial amino acid sequence, VWFCP was identified recently as a ne w member of the ADAMTS family of metalloproteases and designated ADAMTS13. The 4.6-kilo-base pair cDNA sequence for VWFCP has now been determined. By Northern blotting, full-length VWFCP mRNA was detected only in liver. VWFCP consists of 1427 amino acid residues and has a signal peptide, a short pro peptide terminating in the sequence RQRR, a reprolysin-like metalloprotease domain, a disintegrin-like domain, a thrombospondin-1 repeat, a Cys-rich d omain, an ADAMTS spacer, seven additional thrombospondin-1 repeats, and two CUB domains. VWFCP apparently is made as a zymogen that requires proteolyt ic activation, possibly by furin intracellularly. Sites for Zn2+ and Ca2+ i ons are conserved in the protease domain. The Cys-rich domain contains an R GDS sequence that could mediate integrin-dependent binding to platelets or other cells. Alternative splicing gives rise to at least seven potential va riants that truncate the protein at different positions after the protease domain. Alternative splicing may have functional significance, producing pr oteins with distinct abilities to interact with cofactors, connective tissu e, platelets, and von Wiliebrand factor.