Rab7K157N mutant causes CMT

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J Cell Sci. 2009 Jun 16.

Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by

the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5.

Seaman MN, Harbour ME, Tattersall D, Read E, Bright N.

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.