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A more recent version of this article appeared on May 1, 2003
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Submitted on October 10, 2002
Revised on December 23, 2002
Accepted on January 23, 2003
1 Cell and Molecular Biology, Division of Biomedical Sciences, Faculty of Medicine, Imperial College, London SW7 2AZ, UK
2 Cell and Molecular Biology, Division of Biomedical Sciences, Faculty of Medicine, Imperial College, London SW7 2AZ, UK (present address: Centre 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}ic.ac.uk.
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 (REP) and Rab Geranylgeranyl Transferase (RGGT). 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, while mono-cysteine mutants (CSLG, CVLL or CVIM) were mistargeted to the endoplasmic reticulum (ER) and were non-functional. Similarly, Rab27aCVLL mutant is also mistargeted to the ER and transgenic expression on a Rab27a null background (Rab27aash) did not rescue the coat colour 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 REP/RGGT-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.
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