Clathrin-coated vesicles (ccv) play important roles in sorting plasma membrane proteins into the endocytic pathway and sorting proteins between the trans Golgi network (TGN) and endosomes. These ccv-mediated pathways are fundamental, conserved elements of eukaryotic cells; pathway defects can cause inherited human disorders and are likely to contribute to multigenic diseases such as cancer and heart disease. The overall goal of this project is to understand the molecular basis of selective protein transport by ccv in normal cells to provide a foundation for understanding how defects can lead to disease. Towards this goal ccv-mediated protein transport has been characterized in the yeast Saccharomyces cerevisiae. During the previous funding period the actin associated protein Sla1p was identified as a sorting signal recognition factor for NPFX(1,2)D endocytic sorting signals and the Sla1p SHD1 region was defined as a novel sorting signal binding domain. Also, a physiological role for SHD1 in the temporal/spacial regulation of cell wall synthesis was discovered. Based on these advances, genetic, genomic, biochemical, structural, and cell biological approaches will be applied to these specific aims: 1) define the mechanism of cargo recognition by Sla1p during endocytosis; 2) determine the role of Sla1p SHD1 in down-regulating cell wall synthesis; 3) characterize phospho-regulation of SHD1 activity by members of the PKB/Akt kinase subfamily; 4) identify new components of clathrin-mediated endocytic and TGN/endosome trafficking pathways. Together these studies are expected to provide significant advances in understanding the molecular basis and regulation of cargo selection in endocytosis, roles that selective protein recognition can play in cellular physiology, and functions of novel components of the clathrin-based transport machineries that act at the plasma membrane, TGN, and endosomes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Program Officer
Shapiro, Bert I
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Daboussi, Lydia; Costaguta, Giancarlo; Ghukasyan, Razmik et al. (2017) Conserved role for Gga proteins in phosphatidylinositol 4-kinase localization to the trans-Golgi network. Proc Natl Acad Sci U S A 114:3433-3438
Myers, Margaret D; Payne, Gregory S (2017) Vps13 and Cdc31/centrin: Puzzling partners in membrane traffic. J Cell Biol 216:299-301
Myers, Margaret D; Ryazantsev, Sergey; Hicke, Linda et al. (2016) Calmodulin Promotes N-BAR Domain-Mediated Membrane Constriction and Endocytosis. Dev Cell 37:162-73
Myers, Margaret D; Payne, Gregory S (2013) Clathrin, adaptors and disease: insights from the yeast Saccharomyces cerevisiae. Front Biosci (Landmark Ed) 18:862-91
Gorynia, Sabine; Lorenz, Todd C; Costaguta, Giancarlo et al. (2012) Yeast Irc6p is a novel type of conserved clathrin coat accessory factor related to small G proteins. Mol Biol Cell 23:4416-29
Daboussi, Lydia; Costaguta, Giancarlo; Payne, Gregory S (2012) Phosphoinositide-mediated clathrin adaptor progression at the trans-Golgi network. Nat Cell Biol 14:239-48
Hung, Chao-Wei; Aoh, Quyen L; Joglekar, Ajit P et al. (2012) Adaptor autoregulation promotes coordinated binding within clathrin coats. J Biol Chem 287:17398-407
Di Pietro, Santiago M; Cascio, Duilio; Feliciano, Daniel et al. (2010) Regulation of clathrin adaptor function in endocytosis: novel role for the SAM domain. EMBO J 29:1033-44
van der Bliek, Alexander M; Payne, Gregory S (2010) Dynamin subunit interactions revealed. Dev Cell 18:687-8
Anand, Vikram C; Daboussi, Lydia; Lorenz, Todd C et al. (2009) Genome-wide analysis of AP-3-dependent protein transport in yeast. Mol Biol Cell 20:1592-604

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