Fourth International Symposium on Neuroacanthocytosis

Abstracts from the Fourth International Symposium on Neuroacanthocytosis

July 1-2, 2008
London and Oxford

Chairs: Prof. Kailash Bhatia, MD, FRCP, Institute of Neurology, University College London; Prof. Anthony P. Monaco, MD, PhD, Wellcome Trust Centre for Human Genetics, University of Oxford

Organizers: Antonio Velayos-Baeza, PhD; Susanne Schneider, MD; Glenn Irvine

4-1 Soi1/Vps13 in budding yeast
R. S. Fuller, M. E. Abazeed, and M. De
Dept. of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48103, USA

We identified the yeast (Saccharomyces cerevisiae) VPS13 gene through recessive suppressor mutations (soi1 mutations) that affected localization of a trans Golgi Network (TGN) transmembrane (TM) protein, Kex2 protease (Mol. Cell Biol. 1996 16:6208-17; J. Cell Biol. 1997 139:23-36). Vps13p is required for retrograde vesicular transport from the late endosome/PVC (prevacuolar compartment) to the TGN of TM proteins (Kex2p, Ste13p & Vps10p - the lysosomal/vacuolar sorting receptor of yeast) and promotes forward transport of Kex2p and Ste13p from the TGN to the PVC by inhibiting a signal in the cytosolic tails of these proteins that favors retention in TGN, most likely by directing transport between the TGN and early endosome. Vps13p behaves as a peripheral membrane protein that is part of a high molecular mass complex. Three additional observations have been published on Vps13p in yeast that may be of significance for interpreting the function of the Chorea Acanthocytosis protein, Vps13A. First, John Kilmartin published striking evidence that Vps13p is a centrin/Cdc31p-binding protein, and we have obtained some evidence that corroborates this result (J. Cell Biol. 2003 162:1211-21). Centrin is a highly conserved EF-hand protein that binds to several proteins through interaction with a short -helical motif. Calcium binding to the centrin-Sfi1p complex is thought to result in a contractile function at the centriole/spindle pole body. Second, we found that soi1/vps13 null mutants were severely defective for sporulation in yeast. Aaron Nieman and coworkers subsequently found that vps13 mutants are defective for initiation of prospore membrane formation, a process that begins by the recruitment of vesicles to the spindle pole body (J. Cell Sci. 2007 120:908-16). Finally, Michael Sherman and coworkers found vps13 mutations among a collection of mutations that enhance the toxicity of polyQ103 in yeast (Mol. Cell Biol. 2003 23:7554-65). Models that integrate this information will be discussed. We are currently attempting to verify possible Vps13p-interacting proteins identified through high-throughput proteomic screens and to identify additional interactors through mass spectrometric analysis of native and cross-linked complexes isolated from yeast.