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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 (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 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. Social Bookmarking                   What's this? Submitted July 18, 2002 Accepted December 18, 2002 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 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan Department of Transfusion, Osaka University, Osaka, Japan Department of Clinical Pathology, Tokyo Modical College, Tokyo, Japan * Corresponding author; email: yoshi{at}hp-blood.med.osaka-u.ac.jp. 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 type of Glanzmann thrombasthenia. Osaka-12 platelets expressed a substantial amount of IIb3 (36-41% of control) but failed to bind soluble ligands including 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 Tyr143 -> His substitution in IIb and for null expression of IIb mRNA from the maternal allelle. Since Tyr143 is located in 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 previously described KO (Arg-Thr insertion between 160 and 161 residues of IIb) and Asp163Ala mutation located in the same loop by employing 293 cells. Each of them abolished the binding function of IIb3 for soluble ligands without disturbing IIb3 expression. Since immobilized fibrinogen and fibrin are much 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 possessed some ability for cell adhesion and clot retraction. Thus, the functional defect induced by Tyr143HisIIb is likely due to its allosteric effect rather than a defect in ligand binding site itself. These detailed structure-function analyses would provide better understanding of ligand binding sites in integrins. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Gresele, E. Falcinelli, S. Giannini, P. D'Adamo, A. D'Eustacchio, T. Corazzi, A. M. Mezzasoma, F. Di Bari, G. Guglielmini, L. Cecchetti, et al. Dominant inheritance of a novel integrin {beta}3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families Haematologica, May 1, 2009; 94(5): 663 - 669. [Abstract] [Full Text] [PDF] 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]

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