The Talin Head Domain Binds to Integrin β Subunit Cytoplasmic Tails and Regulates Integrin Activation*
- David A. Calderwood‡§,
- Roy Zent‡¶,
- Richard Grant§§,
- D. Jasper G. Rees‖,
- Richard O. Hynes** and
- Mark H. Ginsberg‡‡
- From the ‡Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037,§§Cambridge Molecular, Cambridge CB5 8PB, United Kingdom, the ‖Department of Biochemistry, University of the Western Cape, Bellville 7535, Republic of South Africa, and the **Howard Hughes Medical Institute and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Abstract
The β subunit cytoplasmic domains of integrin adhesion receptors are necessary for the connection of these receptors to the actin cytoskeleton. The cytoplasmic protein, talin, binds to β integrin cytoplasmic tails and actin filaments, hence forming an integrin-cytoskeletal linkage. We used recombinant structural mimics of β1A, β1D and β3integrin cytoplasmic tails to characterize integrin-binding sites within talin. Here we report that an integrin-binding site is localized within the N-terminal talin head domain. The binding of the talin head domain to integrin β tails is specific in that it is abrogated by a single point mutation that disrupts integrin localization to talin-rich focal adhesions. Integrin-cytoskeletal interactions regulate integrin affinity for ligands (activation). Overexpression of a fragment of talin containing the head domain led to activation of integrin αIIbβ3; activation was dependent on the presence of both the talin head domain and the integrin β3 cytoplasmic tail. The head domain of talin thus binds to integrins to form a link to the actin cytoskeleton and can thus regulate integrin function.
Footnotes
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↵* This work was supported by Grants HL48728, HL59007, CA17007, and AR27214 from the National Institutes of Health. This is publication number 12590-VB.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Wellcome Trust International Prize Traveling Fellow.
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↵¶ Fellow of the National Kidney Foundation.
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↵‡ To whom correspondence should be addressed. Tel.: 858-784-7143; Fax: 858-784-7343; E-mail: ginsberg@scripps.edu.
- Abbreviations:
- GST
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glutathioneS-transferase
- PAGE
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polyacrylamide gel electrophoresis
- mAb
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monoclonal antibody
- CHO
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Chinese hamster ovary MFI, median fluorescence intensity
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- Received July 23, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
