title: Saccharomyces cerevisiae Npc2p is a functionally conserved homologue of the human Niemann-Pick disease type C 2 protein, hNPC2.
abstract: Niemann-Pick Disease Type C (NP-C) is a fatal neurodegenerative disease, which is biochemically distinguished by the lysosomal accumulation of exogenously derived cholesterol. Mutation of either the hNPC1 or hNPC2 gene is causative for NP-C. We report the identification of the yeast homologue of human NPC2, Saccharomyces cerevisiae Npc2p. We demonstrate that scNpc2p is evolutionarily related to the mammalian NPC2 family of proteins. We also show, through colocalization, subcellular fractionation, and secretion analyses, that yeast Npc2p is treated similarly to human NPC2 when expressed in mammalian cells. Importantly, we show that yeast Npc2p can efficiently revert the unesterified cholesterol and GM1 accumulation seen in hNPC2-/- patient fibroblasts demonstrating that it is a functional homologue of human NPC2. The present study reveals that the fundamental process of NPC2-mediated lipid transport has been maintained throughout evolution.
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Rd., NE, Atlanta, GA 30322, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Berger
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Vanderford
authors.forename: Kim M
authors.initials: KM
authors.lastname: Gernert
authors.forename: J Wylie
authors.initials: JW
authors.lastname: Nichols
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
authors.forename: Anita H
authors.initials: AH
authors.lastname: Corbett
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D019143:Evolution, Molecular; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005816:Genetic Complementation Test; D006023:Glycoproteins / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C104585:NPC2 protein, human; C508484:Npc2 protein, S cerevisiae; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins; D002784:Cholesterol