Human Molecular Genetics Advance Access originally published online on March 24, 2005
Human Molecular Genetics 2005 14(10):1261-1270; doi:10.1093/hmg/ddi137
© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Comparative evolutionary analysis of VPS33 homologues: genetic and functional insights
Paul Gissen1,2,
Colin A. Johnson1,
Dean Gentle1,
Laurence D. Hurst3,
Aidan J. Doherty4,
Cahir J. O'Kane5,
Deirdre A. Kelly2 and
Eamonn R. Maher1,*
1Section of Medical and Molecular Genetics, University of Birmingham, Birmingham B15 2TG,
2The Liver Unit, Birmingham Children's Hospital, Birmingham B4 6NH, UK,
3Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK,
4UK Genome Damage and Stability Centre, University of Sussex, East Sussex BN1 9RQ, UK and
5Department of Genetics, University of Cambridge, Downing Street CB2 3EH, Cambridge, UK
* To whom correspondence should be addressed. Tel: +44 1216274434; Fax: +44 1214141695; Email: e.r.maher{at}bham.ac.uk
Received December 21, 2004; Accepted March 21, 2005
VPS33B protein is a homologue of the yeast class C vacuolar protein sorting protein Vps33p that is involved in the biogenesis and function of vacuoles. Vps33p homologues contain a Sec1 domain and belong to the family of Sec1/Munc18 (SM) proteins that regulate fusion of membrane-bound organelles and interact with other vps proteins and also SNARE proteins that execute membrane fusion in all cells. We demonstrated recently that mutations in VPS33B cause ARC syndrome (MIM 208085), a lethal multisystem disease. In contrast, mutations in other Vps33p homologues result in different phenotypes, e.g. a mutation in Drosophila melanogaster car gene causes the carnation eye colour mutant and inactivation of mouse Vps33a causes buff hypopigmentation phenotype. In mammals two Vps33p homologues (e.g. VPS33A and VPS33B in humans) have been identified. As comparative genome analysis can provide novel insights into gene evolution and function, we performed nucleotide and protein sequence comparisons of Vps33 homologues in different species to define their inter-relationships and evolution. In silico analysis (a) identified two homologues of yeast Vps33p in the worm, fly, zebrafish, rodent and human genomes, (b) suggested that Carnation is an orthologue of VPS33A rather than VPS33B and (c) identified conserved candidate functional domains within VPS33B. We have shown previously that wild-type VPS33B induced perinuclear clustering of late endosomes and lysosomes in human renal cells. Consistent with the predictions of comparative analysis: (a) VPS33B induced significantly more clustering than VPS33A in a renal cell line, (b) a putative fly VPS33B homologue but not Carnation protein also induced clustering and (c) the ability to induce clustering in renal cells was linked to two evolutionary conserved domains within VPS33B. One domain was present in VPS33B but not VPS33A homologues and the other was one of three regions predicted to form a t-SNARE binding site in VPS33B. In contrast, VPS33A induced significantly more clustering of melanosomes in melanoma cells than VPS33B. These investigations are consistent with the hypothesis that there are two functional classes of Vps33p homologues in all multicellular organisms and that the two classes reflect the evolution of organelle/tissue-specific functions.
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