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Biophysical Analysis of Kindlin-3 Reveals an Elongated Conformation and Maps Integrin Binding to the Membrane-distal β-Subunit NPXY Motif

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      Background: Kindlins are essential co-activators of integrins.

      Results: Kindlin-3 has an elongated structure and forms a ternary complex with the Talin head and integrin β-tails. The Kindlin-3-tail interface involves a membrane-distal NP XY motif on the tail.

      Conclusion: New information about the conformation and interactions of Kindlin-3 has been obtained.

      Significance: The solution structure and protein/protein interactions of Kindlin-3 give insight into its role.


      Kindlin-3, a 75-kDa protein, has been shown to be critical for hemostasis, immunity, and bone metabolism via its role in integrin activation. The Kindlin family is hallmarked by a FERM domain comprised of F1, F2, and F3 subdomains together with an N-terminal F0 domain and a pleckstrin homology domain inserted in the F2 domain. Recombinant Kindlin-3 was cloned, expressed, and purified, and its domain organization was studied by x-ray scattering and other techniques to reveal an extended conformation. This unusual elongated structure is similar to that found in the paralogue Talin head domain. Analytical ultracentrifugation experiments indicated that Kindlin-3 forms a ternary complex with the Talin and β-integrin cytoplasmic tails. NMR showed that Kindlin-3 specifically recognizes the membrane-distal tail NP XY motif in both the β 1A and β 1D isoforms, although the interaction is stronger with β 1A. An upstream Ser/Thr cluster in the tails also plays a critical role. Overall these data support current biological, clinical, and mutational data on Kindlin-3/β-tail binding and provide novel insights into the overall conformation and interactions of Kindlin-3.

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            Author and article information

            From the []Division of Structural Biology, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, United Kingdom and
            the [§ ]Department of Biochemistry, South Parks Road, University of Oxford, Oxford OX1 3QU, United Kingdom
            Author notes
            [4 ] A Royal Society University Research Fellow. To whom correspondence should be addressed: Div. of Structural Biology, Wellcome Trust Centre for Human Genetics, Roosevelt Dr., OX3 7BN. E-mail: gilbert@ .

            Supported by a Medical Research Council (MRC) graduate studentship.


            Supported by Grant U54 GM06434 from the National Institutes of Health-funded Cell Migration Consortium. Present address: Dept. of Pathology, Johns Hopkins University, Baltimore, MD 21287.


            Supported by MRC Grant G0900052 1/1.

            J Biol Chem
            J. Biol. Chem
            The Journal of Biological Chemistry
            American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
            2 November 2012
            18 September 2012
            18 September 2012
            : 287
            : 45
            : 37715-37731
            © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

            Author's Choice—Final version full access.

            Creative Commons Attribution Non-Commercial License applies to Author Choice Articles

            Funded by: National Institutes of Health
            Award ID: U54 GM06434
            Cell Biology


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