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J. Biol. Chem., Vol. 279, Issue 52, 54808-54816, December 24, 2004

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The GAT Domains of Clathrin-associated GGA Proteins Have Two Ubiquitin Binding Motifs^*

Patricia S. Bilodeau, Stanley C. Winistorfer, Margaret M. Allaman¶, Kavitha Surendhran, William R. Kearney¶, Andrew D. Robertson||, and Robert C. Piper**

From the Departments of Physiology and Biophysics and ^||Biochemistry, University of Iowa and the University of Iowa College of Medicine NMR Facility, Iowa City, Iowa 52242

Ubiquitin (Ub) attachment to membrane proteins can serve as a sorting signal for lysosomal delivery. Recognition of Ub as a sorting signal can occur at the trans-Golgi network and is mediated in part by the clathrin-associated Golgi-localizing, -adaptin ear domain homology, ARF-binding proteins (GGA). GGA proteins bind Ub via a three-helix bundle subdomain in their GAT (GGA and target of Myb1 protein) domain, which is also present in the Ub binding domain of target of Myb1 protein. Ubiquitin binding by yeast Ggas is required to direct sorting of ubiquitinated proteins such as general amino acid permease (Gap1) from the trans-Golgi network to endosomes. Using affinity chromatography and nuclear magnetic resonance spectroscopy, we have found that the human GGA3 GAT domain contains two Ub binding motifs that bind to the same surface of ubiquitin. These motifs are found within different helices within the three-helix GAT subdomain. When functionally analyzed in yeast, each motif was sufficient to mediate trans-Golgi network to endosomal sorting of Gap1, and mutation of both motifs resulted in defective Gap1 sorting without defects in other GGA-dependent processes.

Received for publication, June 15, 2004 , and in revised form, October 18, 2004.

^* This work was supported in part by National Institutes of Health Grants GM58202 (to R. C. P.) and GM46869 (to A. D. R.). 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.

^¶ Supported by the University of Iowa College of Medicine.

^** To whom correspondence should be addressed. Tel.: 319-335-7842; Fax: 319-335-7330; E-mail: robert-piper{at}uiowa.edu.

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