Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 14, Issue 5, Pages 406-412Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb1232
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Funding
- NIDDK NIH HHS [P01 DK060564, P01 DK060564-020003, DK60564] Funding Source: Medline
- NIGMS NIH HHS [R01 GM056324-09, GM56324, R01 GM056324] Funding Source: Medline
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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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