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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5609-5616. Prepublished online as a Blood First Edition Paper on February 20, 2009; DOI 10.1182/blood-2008-11-187914. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-11-187914v1 113/22/5609    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 Google Scholar Articles by de Groot, R. Articles by Crawley, J. T. B. PubMed PubMed Citation Articles by de Groot, R. Articles by Crawley, J. T. B. Related Collections Thrombosis and Hemostasis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Essential role of the disintegrin-like domain in ADAMTS13 function Rens de Groot1, Ajoy Bardhan1, Nalisha Ramroop1, David A. Lane1, and James T. B. Crawley1 1 Department of Haematology, Imperial College London, London, United Kingdom ADAMTS13 is a highly specific multidomain plasma metalloprotease that regulates the multimeric size and function of von Willebrand factor (VWF) through cleavage at a single site in the VWF A2 domain. The precise role that the ADAMTS13 disintegrin-like domain plays in its function remains uncertain. Truncated ADAMTS13 variants suggested the importance of the disintegrin-like domain for both enzyme activity and specificity. Targeted mutagenesis of nonconserved regions (among ADAMTS family members) in the disintegrin-like domain identified 3 of 8 ADAMTS13 mutants (R349A, L350G, V352G) with reduced proteolytic activity. Kinetic analyses revealed a 5- to 20-fold reduction in catalytic efficiency of VWF115 (VWF residues 1554-1668) proteolysis by these mutants. These residues form a predicted exposed exosite on the surface of the disintegrin-like domain that lies approximately 26 Å from the active site. Kinetic analysis of VWF115 carrying the D1614A mutation suggested that Arg349 in the ADAMTS13 disintegrin-like domain interacts directly with Asp1614 in VWF A2. We hypothesize that this interaction assists in positioning the scissile bond within the active site of ADAMTS13 and therefore plays a major role in determining cleavage parameters (Km and kcat), as opposed to binding affinity (Kd) of ADAMTS13 for VWF, the latter being primarily determined by the spacer domain. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: A team player: the disintegrin domain of ADAMTS13 X. Long Zheng Blood 2009 113: 5373-5374. [Full Text] [PDF] This article has been cited by other articles: M. Akiyama, S. Takeda, K. Kokame, J. Takagi, and T. Miyata Crystal structures of the noncatalytic domains of ADAMTS13 reveal multiple discontinuous exosites for von Willebrand factor PNAS, November 17, 2009; 106(46): 19274 - 19279. [Abstract] [Full Text] [PDF] S. S. Apte A Disintegrin-like and Metalloprotease (Reprolysin-type) with Thrombospondin Type 1 Motif (ADAMTS) Superfamily: Functions and Mechanisms J. Biol. Chem., November 13, 2009; 284(46): 31493 - 31497. [Abstract] [Full Text] [PDF] 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. L. Zheng A team player: the disintegrin domain of ADAMTS13 Blood, May 28, 2009; 113(22): 5373 - 5374. [Full Text] [PDF]

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