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      Structure analyses reveal a regulated oligomerization mechanism of the PlexinD1/GIPC/myosin VI complex

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          Abstract

          The GIPC family adaptor proteins mediate endocytosis by tethering cargo proteins to the myosin VI motor. The structural mechanisms for the GIPC/cargo and GIPC/myosin VI interactions remained unclear. PlexinD1, a transmembrane receptor that regulates neuronal and cardiovascular development, is a cargo of GIPCs. GIPC-mediated endocytic trafficking regulates PlexinD1 signaling. Here, we unravel the mechanisms of the interactions among PlexinD1, GIPCs and myosin VI by a series of crystal structures of these proteins in apo or bound states. GIPC1 forms a domain-swapped dimer in an autoinhibited conformation that hinders binding of both PlexinD1 and myosin VI. PlexinD1 binding to GIPC1 releases the autoinhibition, promoting its interaction with myosin VI. GIPCs and myosin VI interact through two distinct interfaces and form an open-ended alternating array. Our data support that this alternating array underlies the oligomerization of the GIPC/Myosin VI complexes in solution and cells.

          DOI: http://dx.doi.org/10.7554/eLife.27322.001

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          Semaphorin regulation of cellular morphology.

          Alex Kolodkin, D. R. Bharadwaj, Loan Tran (2006)
          Semaphorin proteins, although initially characterized as repulsive neuronal guidance cues, are now appreciated as major contributors to morphogenesis and homeostasis for a wide range of tissue types. Semaphorin-mediated long- and short-range repulsive, and attractive, guidance has profound influences on cellular morphology. The diversity of semaphorin receptor complexes utilized by various semaphorin ligands, the ability of semaphorins themselves to serve as receptors, and the myriad of intracellular signaling components that comprise semaphorin signaling cascades all contribute to cell-type-specific responses to semaphorins. Analysis of the molecular and cellular mechanisms underlying semaphorin function in neural and vascular systems provides insight into principles governing how this large protein family contributes to organogenesis, function, and disease.
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            The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells.

            K B Avraham, T Hasson, K P Steel … (1995)
            The mouse represents an excellent model system for the study of genetic deafness in humans. Many mouse deafness mutants have been identified and the anatomy of the mouse and human ear is similar. Here we report the use of a positional cloning approach to identify the gene encoded by the mouse recessive deafness mutation, Snell's waltzer (sv). We show that sv encodes an unconventional myosin heavy chain, myosin VI, which is expressed within the sensory hair cells of the inner ear, and appears to be required for maintaining their structural integrity. The requirement for myosin VI in hearing makes this gene an excellent candidate for a human deafness disorder.
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              Structural basis of semaphorin-plexin signalling.

              Eveline P. C. J. Janssen, Menna Jones, W. H. Bell … (2010)
              Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1(1-2)-SEMA4D(ecto) and murine PlxnA2(1-4)-Sema6A(ecto)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto). These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed β-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin-plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity.
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                Author and article information

                Contributors
                Suzanne R Pfeffer: Role: Reviewing editor
                Journal
                Journal ID (nlm-ta): eLife
                Journal ID (iso-abbrev): Elife
                Journal ID (hwp): eLife
                Journal ID (publisher-id): eLife
                Title: eLife
                Publisher: eLife Sciences Publications, Ltd
                ISSN (Electronic): 2050-084X
                Publication date (Electronic, pub): 24 May 2017
                Publication date Collection: 2017
                Volume: 6
                Electronic Location Identifier: e27322
                Affiliations
                [1 ]deptDepartment of Pharmacology , University of Texas Southwestern Medical Center , Dallas, United States
                [2 ]deptDepartment of Biophysics , University of Texas Southwestern Medical Center , Dallas, United States
                [3 ]deptDepartment of Microbiology , University of Texas Southwestern Medical Center , Dallas, United States
                [4 ]deptDepartment of Molecular Biology , University of Texas Southwestern Medical Center , Dallas, United States
                [5 ]deptDepartment of Cell Biology , Skirball Institute of Biomolecular Medicine , New York, United States
                Stanford University School of Medicine , United States
                Stanford University School of Medicine , United States
                Author notes
                Author information
                http://orcid.org/0000-0002-3634-6711
                Article
                Publisher ID: 27322
                DOI: 10.7554/eLife.27322
                PMC ID: 5461112
                PubMed ID: 28537552
                SO-VID: 71d21efe-a3c4-4029-84c1-97cd4aeacab6
                Copyright © © 2017, Shang et al
                License:

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 29 March 2017
                Date accepted : 23 May 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM088197
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000928, Welch Foundation;
                Award ID: I-1702
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01HL133687
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Subject: Research Article
                Subject: Biophysics and Structural Biology
                Custom metadata
                elife-xml-version 2.5
                Author impact statement PlexinD1 binding releases GIPC autoinhibition, leading to formation of high-order oligomers of the GIPC/myosin VI complex.

                ScienceOpen disciplines: Life sciences
                Keywords: plexin,gipc,myosin vi,dimerization,autoinhibition,oligomerization,mouse
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: plexin, gipc, myosin vi, dimerization, autoinhibition, oligomerization, mouse

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