The goal of this research proposal is to define the molecular mechanisms of cargo identification during the earliest event in the sorting of proteins into the multivesicular body (MVB) pathway. Function of the MVB pathway is critical for a number of cellular phenomena. For example, failure to target signaling growth factor receptors into the MVB pathway, for subsequent degradation in the lysosome (""""""""downregulation""""""""), results in prolonged signaling that can contribute to both tumorigenesis and defects in organismal development. Additionally, defects in downregulation of the epithelial sodium channel result in an inherited form of hypertension (Liddle's syndrome). Major Histocompatability Complex II (MHCII)-mediated immune response relies upon the function of an MVB-like structure, the MHCII-compartment. Aberrant trafficking of lipids through this pathway also contributes to a number of human disease states, including atherosclerosis. Finally, many of the functional components of the MVB pathway are usurped by certain viruses during their life cycle (e.g. HIV-1). We have chosen the model eukaryotic organism Saccharomyces cerevisiae to study ? the mechanism of cargo identification and sorting into the MVB pathway. We will utilize an ubiquitinindependent MVB cargo to identify cis- and trans-acting factors that coordinate this poorly understood mode of entry into the MVB pathway. Defining the molecular mechanisms that govern MVB cargo identification, a requisite step that dictates cargo entry into the MVB pathway, will yield significant contributions to the understanding of protein and lipid sorting in normal and disease states. ? ?
| Tan, Jason; Davies, Brian A; Payne, Johanna A et al. (2015) Conformational Changes in the Endosomal Sorting Complex Required for the Transport III Subunit Ist1 Lead to Distinct Modes of ATPase Vps4 Regulation. J Biol Chem 290:30053-65 |
| MacDonald, Chris; Payne, Johanna A; Aboian, Mariam et al. (2015) A family of tetraspans organizes cargo for sorting into multivesicular bodies. Dev Cell 33:328-42 |
| Davies, Brian A; Norgan, Andrew P; Payne, Johanna A et al. (2014) Vps4 stimulatory element of the cofactor Vta1 contacts the ATPase Vps4 ?7 and ?9 to stimulate ATP hydrolysis. J Biol Chem 289:28707-18 |
| Norgan, Andrew P; Davies, Brian A; Azmi, Ishara F et al. (2013) Relief of autoinhibition enhances Vta1 activation of Vps4 via the Vps4 stimulatory element. J Biol Chem 288:26147-56 |
| Shestakova, Anna; Curtiss, Matt; Davies, Brian A et al. (2013) The linker region plays a regulatory role in assembly and activity of the Vps4 AAA ATPase. J Biol Chem 288:26810-9 |
| Norgan, Andrew P; Lee, Jacqueline R E; Oestreich, Andrea J et al. (2012) ESCRT-independent budding of HIV-1 gag virus-like particles from Saccharomyces cerevisiae spheroplasts. PLoS One 7:e52603 |
| Wemmer, Megan; Azmi, Ishara; West, Matthew et al. (2011) Bro1 binding to Snf7 regulates ESCRT-III membrane scission activity in yeast. J Cell Biol 192:295-306 |
| Norgan, Andrew P; Coffman, Paul K; Kocher, Jean-Pierre A et al. (2011) Multilevel Parallelization of AutoDock 4.2. J Cheminform 3:12 |
| Babst, Markus; Davies, Brian A; Katzmann, David J (2011) Regulation of Vps4 during MVB sorting and cytokinesis. Traffic 12:1298-305 |
| Shestakova, Anna; Hanono, Abraham; Drosner, Stacey et al. (2010) Assembly of the AAA ATPase Vps4 on ESCRT-III. Mol Biol Cell 21:1059-71 |
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