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dc.contributor.authorMerithew, Eric Lee
dc.contributor.authorHatherly, Scott
dc.contributor.authorDumas, John J.
dc.contributor.authorLawe, Deirdre C.
dc.contributor.authorHeller-Harrison, Robin A.
dc.contributor.authorLambright, David G.
dc.date2022-08-11T08:09:02.000
dc.date.accessioned2022-08-23T16:15:53Z
dc.date.available2022-08-23T16:15:53Z
dc.date.issued2001-03-30
dc.date.submitted2008-11-21
dc.identifier.citationJ Biol Chem. 2001 Apr 27;276(17):13982-8. Epub 2001 Jan 25. <a href="http://dx.doi.org/10.1074/jbc.M009771200 ">Link to article on publisher's site</a>
dc.identifier.issn0021-9258 (Print)
dc.identifier.doi10.1074/jbc.M009771200
dc.identifier.pmid11278565
dc.identifier.urihttp://hdl.handle.net/20.500.14038/34200
dc.description.abstractRab GTPases function as regulatory components of an evolutionarily conserved machinery that mediates docking, priming, and fusion of vesicles with intracellular membranes. We have previously shown that the active conformation of Rab3A is stabilized by a substantial hydrophobic interface between the putative conformational switch regions (Dumas, J. J., Zhu, Z., Connolly, J. L., and Lambright, D. G. (1999) Structure 7, 413-423). A triad of invariant hydrophobic residues at this switch interface (Phe-59, Trp-76, and Tyr-91) represents a major interaction determinant between the switch regions of Rab3A and the Rab3A-specific effector Rabphilin3A (Ostermeier, C., and Brunger, A. T. (1999) Cell 96, 363-374). Here, we report the crystal structure of the active form of Rab5C, a prototypical endocytic Rab GTPase. As is true for Rab3A, the active conformation of Rab5C is stabilized by a hydrophobic interface between the switch regions. However, the conformation of the invariant hydrophobic triad (residues Phe-58, Trp-75, and Tyr-90 in Rab5C) is dramatically altered such that the resulting surface is noncomplementary to the switch interaction epitope of Rabphilin3A. This structural rearrangement reflects a set of nonconservative substitutions in the hydrophobic core between the central beta sheet and the alpha2 helix. These observations demonstrate that structural plasticity involving an invariant hydrophobic triad at the switch interface contributes to the mechanism by which effectors recognize distinct Rab subfamilies. Thus, the active conformation of the switch regions conveys information about the identity of a particular Rab GTPase as well as the state of the bound nucleotide.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11278565&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1074/jbc.M009771200
dc.subjectAdaptor Proteins, Signal Transducing; Amino Acid Sequence; Base Sequence; Crystallography, X-Ray; Epitopes; Escherichia coli; Models, Molecular; Molecular Sequence Data; Nerve Tissue Proteins; Phenylalanine; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Tryptophan; Tyrosine; Vesicular Transport Proteins; rab GTP-Binding Proteins; rab3A GTP-Binding Protein; rab5 GTP-Binding Proteins
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleStructural plasticity of an invariant hydrophobic triad in the switch regions of Rab GTPases is a determinant of effector recognition
dc.typeJournal Article
dc.source.journaltitleThe Journal of biological chemistry
dc.source.volume276
dc.source.issue17
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/857
dc.identifier.contextkey670513
html.description.abstract<p>Rab GTPases function as regulatory components of an evolutionarily conserved machinery that mediates docking, priming, and fusion of vesicles with intracellular membranes. We have previously shown that the active conformation of Rab3A is stabilized by a substantial hydrophobic interface between the putative conformational switch regions (Dumas, J. J., Zhu, Z., Connolly, J. L., and Lambright, D. G. (1999) Structure 7, 413-423). A triad of invariant hydrophobic residues at this switch interface (Phe-59, Trp-76, and Tyr-91) represents a major interaction determinant between the switch regions of Rab3A and the Rab3A-specific effector Rabphilin3A (Ostermeier, C., and Brunger, A. T. (1999) Cell 96, 363-374). Here, we report the crystal structure of the active form of Rab5C, a prototypical endocytic Rab GTPase. As is true for Rab3A, the active conformation of Rab5C is stabilized by a hydrophobic interface between the switch regions. However, the conformation of the invariant hydrophobic triad (residues Phe-58, Trp-75, and Tyr-90 in Rab5C) is dramatically altered such that the resulting surface is noncomplementary to the switch interaction epitope of Rabphilin3A. This structural rearrangement reflects a set of nonconservative substitutions in the hydrophobic core between the central beta sheet and the alpha2 helix. These observations demonstrate that structural plasticity involving an invariant hydrophobic triad at the switch interface contributes to the mechanism by which effectors recognize distinct Rab subfamilies. Thus, the active conformation of the switch regions conveys information about the identity of a particular Rab GTPase as well as the state of the bound nucleotide.</p>
dc.identifier.submissionpathgsbs_sp/857
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pages13982-8


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