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Title: Structural Basis for Rab GTPase Activation by VPS9 Domain Exchange Factors

Abstract

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.

Authors:
;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930422
Report Number(s):
BNL-81157-2008-JA
Journal ID: ISSN 1545-9993; TRN: US200904%%699
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Structural and Molecular Biology; Journal Volume: 14; Journal Issue: 5
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; GTP-ASES; MUTATIONS; PROTEINS; RESIDUES; SUBSTRATES; national synchrotron light source

Citation Formats

Delprato,A., and Lambright, D. Structural Basis for Rab GTPase Activation by VPS9 Domain Exchange Factors. United States: N. p., 2007. Web. doi:10.1038/nsmb1232.
Delprato,A., & Lambright, D. Structural Basis for Rab GTPase Activation by VPS9 Domain Exchange Factors. United States. doi:10.1038/nsmb1232.
Delprato,A., and Lambright, D. Mon . "Structural Basis for Rab GTPase Activation by VPS9 Domain Exchange Factors". United States. doi:10.1038/nsmb1232.
@article{osti_930422,
title = {Structural Basis for Rab GTPase Activation by VPS9 Domain Exchange Factors},
author = {Delprato,A. and Lambright, D.},
abstractNote = {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.},
doi = {10.1038/nsmb1232},
journal = {Nature Structural and Molecular Biology},
number = 5,
volume = 14,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}