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J. Biol. Chem., Vol. 283, Issue 49, 34188-34196, December 5, 2008

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A C-terminal Sequence in the Guanine Nucleotide Exchange Factor Sec7 Mediates Golgi Association and Interaction with the Rsp5 Ubiquitin Ligase^*

From the Department of Biochemistry, Molecular Biology & Cell Biology, Northwestern University, Evanston, Illinois 60208

Arf GTPases control vesicle formation from different intracellular membranes and are regulated by Arf guanine nucleotide exchange factors (GEFs). Outside of their conserved catalytic domains, known as Sec7 domains, little is known about Arf GEFs. Rsp5 is a yeast ubiquitin ligase that regulates numerous membrane trafficking events and carries a C2 domain that is specifically required for trans-Golgi network to vacuole transport. In a screen for proteins that interact with the Rsp5 C2 domain we identified Sec7, the GEF that acts on Golgi-associated Arfs. The Rsp5-Sec7 interaction is direct, occurs in vivo, and is conserved among mammalian Rsp5 and Sec7 homologues. A 50-amino acid region near the Sec7 C terminus is required for Rsp5 binding and for normal Sec7 localization. Binding of Sec7 to Rsp5 is dependent on the presence of the phosphoinositide 3-kinase Vps34, suggesting that phosphatidylinositol 3-phosphate (PI(3)P) plays a role in regulating this interaction. Overexpression of Sec7 significantly suppresses the growth and sorting defects of an rsp5 C2 domain point mutant. These observations identify a new functional region within the Sec7/BIG family of Arf GEFs that is required for trans-Golgi network localization.

Received for publication, August 5, 2008 , and in revised form, September 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK53257 and DK61299 (to L. H.) and Training Grant T32GM08061 (to D. A. K. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104.

² Present address: Dept. of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305.

³ Present address: Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.

⁴ To whom correspondence should be addressed: Hogan Hall 2–100, 2205 Tech Dr., Evanston, IL 60208. Fax: 847-491-4970; E-mail: l-hicke{at}northwestern.edu.

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