We are upgrading the repository! A content freeze is in effect until December 6, 2024. New submissions or changes to existing items will not be allowed during this period. All content already published will remain publicly available for searching and downloading. Updates will be posted in the Website Upgrade 2024 FAQ in the sidebar Help menu. Reach out to escholarship@umassmed.edu with any questions.
Structural plasticity of an invariant hydrophobic triad in the switch regions of Rab GTPases is a determinant of effector recognition
Authors
Merithew, Eric LeeHatherly, Scott
Dumas, John J.
Lawe, Deirdre C.
Heller-Harrison, Robin A.
Lambright, David G.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyProgram in Molecular Medicine
Morningside Graduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2001-03-30
Metadata
Show full item recordAbstract
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.Source
J Biol Chem. 2001 Apr 27;276(17):13982-8. Epub 2001 Jan 25. Link to article on publisher's siteDOI
10.1074/jbc.M009771200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/34200PubMed ID
11278565Related Resources
Link to article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M009771200