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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-07-2144. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-07-2144v1 101/9/3485    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 Kiyoi, T. Articles by Matsuzawa, Y. Search for Related Content PubMed PubMed Citation Articles by Kiyoi, T. Articles by Matsuzawa, Y. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 May 2003, Vol. 101, No. 9, pp. 3485-3491 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY A naturally occurring Tyr143HisIIb mutation abolishes IIb3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects Teruo Kiyoi, Yoshiaki Tomiyama, Shigenori Honda, Seiji Tadokoro, Morio Arai, Hirokazu Kashiwagi, Satoru Kosugi, Hisashi Kato, Yoshiyuki Kurata, and Yuji Matsuzawa From the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University; the Department of Blood Transfusion, Osaka University Hospital; and the Department of Laboratory Medicine, Tokyo Medical University, Japan. The molecular basis for the interaction between a prototypic non-I-domain integrin, IIb3, and its ligands remains to be determined. In this study, we have characterized a novel missense mutation (Tyr143His) in IIb associated with a variant of Glanzmann thrombasthenia. Osaka-12 platelets expressed a substantial amount of IIb3 (36%-41% of control) but failed to bind soluble ligands, including a high-affinity IIb3-specific peptidomimetic antagonist. Sequence analysis revealed that Osaka-12 is a compound heterozygote for a single 521T>C substitution leading to a Tyr143His substitution in IIb and for the null expression of IIb mRNA from the maternal allele. Given that Tyr143 is located in the W3 4-1 loop of the -propeller domain of IIb, we examined the effects of Tyr143His or Tyr143Ala substitution on the expression and function of IIb3 and compared them with KO (Arg-Thr insertion between 160 and 161 residues of IIb) and with the Asp163Ala mutation located in the same loop by using 293 cells. Each of them abolished the binding function of IIb3 for soluble ligands without disturbing IIb3 expression. Because immobilized fibrinogen and fibrin are higher affinity/avidity ligands for IIb3, we performed cell adhesion and clot retraction assays. In sharp contrast to KO mutation and Asp163AlaIIb3, Tyr143HisIIb3-expressing cells still had some ability for cell adhesion and clot retraction. Thus, the functional defect induced by Tyr143HisIIb is likely caused by its allosteric effect rather than by a defect in the ligand-binding site itself. These detailed structure-function analyses provide better understanding of the ligand-binding sites in integrins. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Kashiwagi, M. Shiraga, H. Kato, T. Kamae, N. Yamamoto, S. Tadokoro, Y. Kurata, Y. Tomiyama, and Y. Kanakura Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A Blood, August 1, 2005; 106(3): 913 - 921. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020