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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1887-1894. Prepublished online as a Blood First Edition Paper on May 31, 2007; DOI 10.1182/blood-2007-04-083329. This Article Full Text (PDF) All Versions of this Article: blood-2007-04-083329v1 110/6/1887    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhang, P. Articles by Zheng, X. L. Search for Related Content PubMed PubMed Citation Articles by Zhang, P. Articles by Zheng, X. L. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 3, 2007 Accepted May 29, 2007 The cooperative activity between the carboxyl-terminal TSP-1 repeats and the CUB domains of ADAMTS13 is crucial for recognition of von Willebrand factor under flow Ping Zhang, Weilan Pan, Ann H. Rux, Bruce S. Sachais, and X. Long Zheng* Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, PA, United States * Corresponding author; email: zheng{at}email.chop.edu. ADAMTS13 cleaves von Willebrand factor (VWF) between Tyr1605 and Met1606 residues at the central A2 subunit. The amino-terminus of ADAMTS13 protease appears to be sufficient to bind and cleave VWF under static and denatured condition. However, the role of the carboxyl-terminus of ADAMTS13 in substrate recognition remains controversial. Present study demonstrates that ADAMTS13 cleaves VWF in a rotation speed- and protease concentration-dependent manner on a mini-vortexer. Removal of the CUB domains (delCUB) or truncation after the spacer domain (MDTCS) abolishes its ability to cleave VWF under the same condition. ADAMTS13 and delCUB (but not MDTCS) bind VWF under flow with dissociation constants (KD) of ~50 nM and ~274 nM, respectively. The isolated CUB domains are neither sufficient to bind VWF detectably, nor capable of inhibiting proteolytic cleavage of VWF by ADAMTS13 under flow. Addition of the TSP1 5-8 (T5-8CUB) or TSP1 2-8 repeats (T2-8CUB) to the CUB domains restores the binding affinity toward VWF and the inhibitory effect on cleavage of VWF by ADAMTS13 under flow. These data demonstrate directly and quantitatively that the cooperative activity between the middle carboxyl-terminal TSP1 repeats and the distal carboxyl-terminal CUB domains may be crucial for recognition and cleavage of VWF under flow. 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