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Vol. 14, Issue 5, 1882-1899, May 2003
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Cell and Molecular Biology, Division of Biomedical Sciences, Faculty of Medicine, Imperial College, London SW7 2AZ, United Kingdom
Submitted October 10, 2002;
Revised December 23, 2002;
Accepted January 23, 2003
Monitoring Editor: Suzanne Pfeffer
Rab GTPases are regulators of membrane traffic. Rabs specifically associate
with target membranes via the attachment of (usually) two geranylgeranyl
groups in a reaction involving Rab escort protein and Rab geranylgeranyl
transferase. In contrast, related GTPases are singly prenylated by
CAAX prenyl transferases. We report that di-geranylgeranyl
modification is important for targeting of Rab5a and Rab27a to endosomes and
melanosomes, respectively. Transient expression of EGFP-Rab5 mutants
containing two prenylatable cysteines (CGC, CC, CCQNI, and CCA) in HeLa cells
did not affect endosomal targeting or function, whereas mono-cysteine mutants
(CSLG, CVLL, or CVIM) were mistargeted to the endoplasmic reticulum (ER) and
were nonfunctional. Similarly, Rab27aCVLL mutant is also mistargeted to the ER
and transgenic expression on a Rab27a null background
(Rab27aash) did not rescue the coat color phenotype,
suggesting that Rab27aCVLL is not functional in vivo. CAAX prenyl
transferase inhibition and temperature-shift experiments further suggest that
Rabs, singly or doubly modified are recruited to membranes via a Rab escort
protein/Rab geranylgeranyl transferase-dependent mechanism that is distinct
from the insertion of CAAX-containing GTPases. Finally, we show that
both singly and doubly modified Rabs are extracted from membranes by
RabGDI
and propose that the mistargeting of Rabs to the ER results from
loss of targeting information.
Online version of this article contains supplemental figure materials.
Online version available at
http://www.molbiolcell.org.
* Present address: Center of Ophthalmology, University of Coimbra, Biomedical Institute for Research in Light and Image, Azinhaga Sta. Comba, 3000-354 Coimbra, Portugal.
Corresponding author. E-mail address:
m.seabra{at}imperial.ac.uk.
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