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dc.contributor.authorDas, Sanchaita
dc.contributor.authorMalaby, Andrew W.
dc.contributor.authorNawrotek, Agata
dc.contributor.authorZhang, Wenhua
dc.contributor.authorZeghouf, Mahel
dc.contributor.authorMaslen, Sarah
dc.contributor.authorSkehel, Mark
dc.contributor.authorChakravarthy, Srinivas
dc.contributor.authorIrving, Thomas C.
dc.contributor.authorBilsel, Osman
dc.contributor.authorCherfils, Jacqueline
dc.contributor.authorLambright, David G.
dc.date2022-08-11T08:09:55.000
dc.date.accessioned2022-08-23T16:48:44Z
dc.date.available2022-08-23T16:48:44Z
dc.date.issued2019-12-03
dc.date.submitted2020-01-21
dc.identifier.citation<p>Structure. 2019 Dec 3;27(12):1782-1797.e7. doi: 10.1016/j.str.2019.09.007. Epub 2019 Oct 7. <a href="https://doi.org/10.1016/j.str.2019.09.007">Link to article on publisher's site</a></p>
dc.identifier.issn0969-2126 (Linking)
dc.identifier.doi10.1016/j.str.2019.09.007
dc.identifier.pmid31601460
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41324
dc.description.abstractMembrane dynamic processes require Arf GTPase activation by guanine nucleotide exchange factors (GEFs) with a Sec7 domain. Cytohesin family Arf GEFs function in signaling and cell migration through Arf GTPase activation on the plasma membrane and endosomes. In this study, the structural organization of two cytohesins (Grp1 and ARNO) was investigated in solution by size exclusion-small angle X-ray scattering and negative stain-electron microscopy and on membranes by dynamic light scattering, hydrogen-deuterium exchange-mass spectrometry and guanosine diphosphate (GDP)/guanosine triphosphate (GTP) exchange assays. The results suggest that cytohesins form elongated dimers with a central coiled coil and membrane-binding pleckstrin-homology (PH) domains at opposite ends. The dimers display significant conformational heterogeneity, with a preference for compact to intermediate conformations. Phosphoinositide-dependent membrane recruitment is mediated by one PH domain at a time and alters the conformational dynamics to prime allosteric activation by Arf-GTP. A structural model for membrane targeting and allosteric activation of full-length cytohesin dimers is discussed.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31601460&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectDLS
dc.subjectEM
dc.subjectGEF
dc.subjectHDX
dc.subjectMS
dc.subjectNS
dc.subjectSAXS
dc.subjectSEC
dc.subjectautoinhibition
dc.subjectstructure
dc.subjectBiochemistry
dc.subjectBiophysics
dc.subjectMolecular Biology
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.subjectStructural Biology
dc.titleStructural Organization and Dynamics of Homodimeric Cytohesin Family Arf GTPase Exchange Factors in Solution and on Membranes
dc.typeJournal Article
dc.source.journaltitleStructure (London, England : 1993)
dc.source.volume27
dc.source.issue12
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5128&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4109
dc.identifier.contextkey16292500
refterms.dateFOA2022-08-23T16:48:44Z
html.description.abstract<p>Membrane dynamic processes require Arf GTPase activation by guanine nucleotide exchange factors (GEFs) with a Sec7 domain. Cytohesin family Arf GEFs function in signaling and cell migration through Arf GTPase activation on the plasma membrane and endosomes. In this study, the structural organization of two cytohesins (Grp1 and ARNO) was investigated in solution by size exclusion-small angle X-ray scattering and negative stain-electron microscopy and on membranes by dynamic light scattering, hydrogen-deuterium exchange-mass spectrometry and guanosine diphosphate (GDP)/guanosine triphosphate (GTP) exchange assays. The results suggest that cytohesins form elongated dimers with a central coiled coil and membrane-binding pleckstrin-homology (PH) domains at opposite ends. The dimers display significant conformational heterogeneity, with a preference for compact to intermediate conformations. Phosphoinositide-dependent membrane recruitment is mediated by one PH domain at a time and alters the conformational dynamics to prime allosteric activation by Arf-GTP. A structural model for membrane targeting and allosteric activation of full-length cytohesin dimers is discussed.</p>
dc.identifier.submissionpathoapubs/4109
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentProgram in Molecular Medicine
dc.source.pages1782-1797.e7


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Copyright 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as Copyright 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).