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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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      Abstract

      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.

      Abstract

      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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      Most cited references 52

      • Record: found
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      UCSF Chimera--a visualization system for exploratory research and analysis.

      The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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        NMRPipe: a multidimensional spectral processing system based on UNIX pipes.

        The NMRPipe system is a UNIX software environment of processing, graphics, and analysis tools designed to meet current routine and research-oriented multidimensional processing requirements, and to anticipate and accommodate future demands and developments. The system is based on UNIX pipes, which allow programs running simultaneously to exchange streams of data under user control. In an NMRPipe processing scheme, a stream of spectral data flows through a pipeline of processing programs, each of which performs one component of the overall scheme, such as Fourier transformation or linear prediction. Complete multidimensional processing schemes are constructed as simple UNIX shell scripts. The processing modules themselves maintain and exploit accurate records of data sizes, detection modes, and calibration information in all dimensions, so that schemes can be constructed without the need to explicitly define or anticipate data sizes or storage details of real and imaginary channels during processing. The asynchronous pipeline scheme provides other substantial advantages, including high flexibility, favorable processing speeds, choice of both all-in-memory and disk-bound processing, easy adaptation to different data formats, simpler software development and maintenance, and the ability to distribute processing tasks on multi-CPU computers and computer networks.
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          • Record: found
          • Abstract: found
          • Article: not found

          Integrins: bidirectional, allosteric signaling machines.

          In their roles as major adhesion receptors, integrins signal across the plasma membrane in both directions. Recent structural and cell biological data suggest models for how integrins transmit signals between their extracellular ligand binding adhesion sites and their cytoplasmic domains, which link to the cytoskeleton and to signal transduction pathways. Long-range conformational changes couple these functions via allosteric equilibria.
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            Author and article information

            Affiliations
            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@ 123456strubi.ox.ac.uk .
            [1]

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

            [2]

            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.

            [3]

            Supported by MRC Grant G0900052 1/1.

            Journal
            J Biol Chem
            J. Biol. Chem
            jbc
            jbc
            JBC
            The Journal of Biological Chemistry
            American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
            0021-9258
            1083-351X
            2 November 2012
            18 September 2012
            18 September 2012
            : 287
            : 45
            : 37715-37731
            22989875
            3488048
            M112.415208
            10.1074/jbc.M112.415208
            © 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

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

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