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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1713-1719. Prepublished online as a Blood First Edition Paper on May 20, 2008; DOI 10.1182/blood-2008-04-148759. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-04-148759v1 112/5/1713    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Gao, W. Articles by Sadler, J. E. Search for Related Content PubMed PubMed Citation Articles by Gao, W. Articles by Sadler, J. E. Related Collections Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Extensive contacts between ADAMTS13 exosites and von Willebrand factor domain A2 contribute to substrate specificity Weiqiang Gao1, Patricia J. Anderson1, and J. Evan Sadler1 1 Department of Medicine, Department of Biochemistry and Molecular Biophysics, and Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO The metalloprotease ADAMTS13 efficiently cleaves only the Tyr1605-Met1606 bond in the central A2 domain of multimeric von Willebrand factor (VWF), even though VWF constitutes only 0.02% of plasma proteins. This remarkable specificity depends in part on binding of the noncatalytic ADAMTS13 spacer domain to the C-terminal -helix of VWF domain A2. By kinetic analysis of recombinant ADAMTS13 constructs, we show that the first thrombospondin-1, Cys-rich, and spacer domains of ADAMTS13 interact with segments of VWF domain A2 between Gln1624 and Arg1668, and together these exosite interactions increase the rate of substrate cleavage by at least approximately 300-fold. Internal deletion of Gln1624-Arg1641 minimally affected the rate of cleavage, indicating that ADAMTS13 does not require a specific distance between the scissile bond and auxiliary substrate binding sites. Smaller deletions of the P2-P9 or the P4'-P18' residues on either side of the Tyr1605-Met1606 bond abolished cleavage, indicating that the metalloprotease domain interacts with additional residues flanking the cleavage site. Thus, specific recognition of VWF depends on cooperative, modular contacts between several ADAMTS13 domains and discrete segments of VWF domain A2. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Shear tango: dance of the ADAMTS13/VWF complex Rens de Groot and David A. Lane Blood 2008 112: 1548-1549. [Full Text] [PDF] This article has been cited by other articles: S. Zanardelli, A. C. K. Chion, E. Groot, P. J. Lenting, T. A. J. McKinnon, M. A. Laffan, M. Tseng, and D. A. Lane A novel binding site for ADAMTS13 constitutively exposed on the surface of globular VWF Blood, September 24, 2009; 114(13): 2819 - 2828. [Abstract] [Full Text] [PDF] X. Zhang, K. Halvorsen, C.-Z. Zhang, W. P. Wong, and T. A. Springer Mechanoenzymatic Cleavage of the Ultralarge Vascular Protein von Willebrand Factor Science, June 5, 2009; 324(5932): 1330 - 1334. [Abstract] [Full Text] [PDF] X. L. Zheng A team player: the disintegrin domain of ADAMTS13 Blood, May 28, 2009; 113(22): 5373 - 5374. [Full Text] [PDF] R. de Groot, A. Bardhan, N. Ramroop, D. A. Lane, and J. T. B. Crawley Essential role of the disintegrin-like domain in ADAMTS13 function Blood, May 28, 2009; 113(22): 5609 - 5616. [Abstract] [Full Text] [PDF]

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