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First published online 16 June 2009
doi: 10.1242/jcs.048686

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Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5

Matthew N. J. Seaman^*, Michael E. Harbour, Daniel Tattersall, Eliot Read and Nicholas Bright

University of Cambridge, Cambridge Institute for Medical Research, Department of Clinical Biochemistry, Wellcome Trust/MRC Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 0XY, UK

^* Author for correspondence (e-mail: mnjs100{at}cam.ac.uk)

Accepted 24 March 2009

Retromer is a membrane-associated heteropentameric coat complex that functions in the endosome-to-Golgi retrieval of the cation-independent mannose-6-phosphate receptor, the Wntless protein and other membrane proteins of physiological significance. Retromer comprises two functional subcomplexes: the cargo-selective subcomplex is a trimer of the VPS35, VPS29, VPS26 proteins, whereas the sorting nexin proteins, Snx1 and Snx2 function to tubulate the endosomal membrane. Unlike the sorting nexins, which contain PtdIns3P-binding PX domains, the cargo-selective VPS35/29/26 complex has no lipid-binding domains and its recruitment to the endosomal membrane remains mechanistically uncharacterised. In this study we show that the VPS35/29/26 complex interacts with the small GTPase Rab7 and requires Rab7 for its recruitment to the endosome. We show that the Rab7K157N mutant that causes the peripheral neuropathy, Charcot-Marie-Tooth disease, does not interact with the VPS35/29/26 complex, resulting in a weakened association with the membrane. We have also identified a novel retromer-interacting protein, TBC1D5, which is a member of the Rab GAP family of proteins that negatively regulates VPS35/29/26 recruitment and causes Rab7 to dissociate from the membrane. We therefore propose that recruitment of the cargo-selective VPS35/29/26 complex is catalysed by Rab7 and inhibited by the Rab-GAP protein, TBC1D5.

Key words: Endosome, Rab-GAP, Rab7, Recruitment, Retromer

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