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Vol. 19, Issue 5, 1991-2002, May 2008

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The Clathrin Adaptor Gga2p Is a Phosphatidylinositol 4-phosphate Effector at the Golgi Exit

Lars Demmel^,*, Maike Gravert^,*, Ebru Ercan, Bianca Habermann, Thomas Müller-Reichert, Viktoria Kukhtina, Volker Haucke, Thorsten Baust^||, Marc Sohrmann^¶, Yannis Kalaidzidis^,#, Christian Klose, Mike Beck, Matthias Peter^¶, and Christiane Walch-Solimena

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, D-01307, Germany; Scionics Computer Innovation, Dresden, D-01307, Germany; Chemistry-Biochemistry, Free University, Berlin, D-14195, Germany; ^||Biotechnological Centre (BIOTEC), Technological University, Dresden, D-01307, Germany; ^¶Institute of Biochemistry, Swiss Federal Institute of Technology Zürich (ETH), Zürich, Ch-8093, Switzerland; and ^#A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119899, Russia

Submitted October 20, 2006; Revised January 29, 2008; Accepted February 11, 2008
Monitoring Editor: Benjamin Glick

Phosphatidylinositol 4-phosphate (PI(4)P) is a key regulator of membrane transport required for the formation of transport carriers from the trans-Golgi network (TGN). The molecular mechanisms of PI(4)P signaling in this process are still poorly understood. In a search for PI(4)P effector molecules, we performed a screen for synthetic lethals in a background of reduced PI(4)P and found the gene GGA2. Our analysis uncovered a PI(4)P-dependent recruitment of the clathrin adaptor Gga2p to the TGN during Golgi-to-endosome trafficking. Gga2p recruitment to liposomes is stimulated both by PI(4)P and the small GTPase Arf1p in its active conformation, implicating these two molecules in the recruitment of Gga2p to the TGN, which ultimately controls the formation of clathrin-coated vesicles. PI(4)P binding occurs through a phosphoinositide-binding signature within the N-terminal VHS domain of Gga2p resembling a motif found in other clathrin interacting proteins. These data provide an explanation for the TGN-specific membrane recruitment of Gga2p.

* These authors contributed equally to this work.

Address correspondence to: Christiane Walch-Solimena (csolimena{at}mpi-cbg.de)

Abbreviations used: CPY, carboxypeptidase Y; PtdIns, phosphatidylinositol; PI(3)P, phosphatidylinositol (3)-phosphate; PI(4)P, phosphatidylinositol (4)-phosphate; PI(3,5)P₂, phosphatidylinositol (3,5)-bisphosphate; PI(4,5)P₂, phosphatidylinositol (4,5)-bisphosphate; PI, phosphoinositide; SGA, synthetic genetic array; SPR, surface plasmon resonance; SV, secretory vesicle; TGN, trans-Golgi network.

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