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Vol. 20, Issue 1, 209-217, January 1, 2009

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Multiple Rab GTPase Binding Sites in GCC185 Suggest a Model for Vesicle Tethering at the Trans-Golgi

Garret L. Hayes^*, Frank C. Brown^*, Alexander K. Haas, Ryan M. Nottingham^*, Francis A. Barr, and Suzanne R. Pfeffer^*

*Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305; and Cancer Research Centre, University of Liverpool, Liverpool L9 3AT, United Kingdom

Submitted July 18, 2008; Revised September 22, 2008; Accepted October 14, 2008
Monitoring Editor: Vivek Malhotra

GCC185, a trans-Golgi network-localized protein predicted to assume a long, coiled-coil structure, is required for Rab9-dependent recycling of mannose 6-phosphate receptors (MPRs) to the Golgi and for microtubule nucleation at the Golgi via CLASP proteins. GCC185 localizes to the Golgi by cooperative interaction with Rab6 and Arl1 GTPases at adjacent sites near its C terminus. We show here by yeast two-hybrid and direct biochemical tests that GCC185 contains at least four additional binding sites for as many as 14 different Rab GTPases across its entire length. A central coiled-coil domain contains a specific Rab9 binding site, and functional assays indicate that this domain is important for MPR recycling to the Golgi complex. N-Terminal coiled-coils are also required for GCC185 function as determined by plasmid rescue after GCC185 depletion by using small interfering RNA in cultured cells. Golgi-Rab binding sites may permit GCC185 to contribute to stacking and lateral interactions of Golgi cisternae as well as help it function as a vesicle tether.

Address correspondence to: Suzanne R. Pfeffer (pfeffer{at}stanford.edu).

Abbreviations used: MPR, mannose 6-phosphate receptor; TGN, trans-Golgi network.