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Molecular and Cellular Biology, December 2001, p. 7981-7994, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.7981-7994.2001

Structural Requirements for Function of Yeast GGAs in Vacuolar Protein Sorting, alpha -Factor Maturation, and Interactions with Clathrin

Chris Mullins and Juan S. Bonifacino*

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-5430

Received 4 June 2001/Returned for modification 27 June 2001/Accepted 4 September 2001

The GGAs (Golgi-localized, gamma-ear-containing, ARF-binding proteins) are a family of multidomain adaptor proteins involved in protein sorting at the trans-Golgi network of eukaryotic cells. Here we present results from a functional characterization of the two Saccharomyces cerevisiae GGAs, Gga1p and Gga2p. We show that deletion of both GGA genes causes defects in sorting of carboxypeptidase Y (CPY) and proteinase A to the vacuole, vacuolar morphology, and maturation of alpha -factor. A structure-function analysis reveals a requirement of the VHS, GAT, and hinge for function, while the GAE domain is less important. We identify putative clathrin-binding motifs in the hinge domain of both yeast GGAs. These motifs are shown to mediate clathrin binding in vitro. While mutation of these motifs alone does not block function of the GGAs in vivo, combining these mutations with truncations of the hinge and GAE domains diminishes function, suggesting functional cooperation between different clathrin-binding elements. Thus, these observations demonstrate that the yeast GGAs play important roles in the CPY pathway, vacuole biogenesis, and alpha -factor maturation and identify structural determinants that are critical for these functions.

* Corresponding author. Mailing address: CBMB, NICHD, National Institutes of Health, Bldg. 18T, Room 101, 18 Library Dr. MSC 5430, Bethesda, MD 20892-5430. Phone: (301) 496-6368. Fax: (301) 402-0078. E-mail: juan{at}helix.nih.gov.

Molecular and Cellular Biology, December 2001, p. 7981-7994, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.7981-7994.2001


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