Structural basis for Rab GTPase activation by VPS9 domain exchange factors
Program in Molecular Medicine and Department of Biochemistry and Molecular Pharmacology
Binding Sites; Crystallography, X-Ray; Enzyme Activation; Guanine Nucleotide Exchange Factors; Guanosine Diphosphate; Humans; Mutation; Protein Conformation; Vesicular Transport Proteins; rab GTP-Binding Proteins
Life Sciences | Medicine and Health Sciences
RABEX-5 and other exchange factors with VPS9 domains regulate endocytic trafficking through activation of the Rab family GTPases RAB5, RAB21 and RAB22. Here we report the crystal structure of the RABEX-5 catalytic core in complex with nucleotide-free RAB21, a key intermediate in the exchange reaction pathway. The structure reveals how VPS9 domain exchange factors recognize Rab GTPase substrates, accelerate GDP release and stabilize the nucleotide-free conformation. We further identify an autoinhibitory element in a predicted amphipathic helix located near the C terminus of the VPS9 domain. The autoinhibitory element overlaps with the binding site for the multivalent effector RABAPTIN-5 and potently suppresses the exchange activity of RABEX-5. Autoinhibition can be partially reversed by mutation of conserved residues on the nonpolar face of the predicted amphipathic helix or by assembly of the complex with RABAPTIN-5.
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Citation: Nat Struct Mol Biol. 2007 May;14(5):406-12. Epub 2007 Apr 22. Link to article on publisher's site
DOI of Published Version
Nature structural and molecular biology
Delprato, Anna M. and Lambright, David G., "Structural basis for Rab GTPase activation by VPS9 domain exchange factors" (2007). Open Access Articles. 1337.