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Eukaryotic Cell, November 2005, p. 1851-1862, Vol. 4, No. 11
1535-9778/05/$08.00+0     doi:10.1128/EC.4.11.1851-1862.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Saccharomyces cerevisiae Npc2p Is a Functionally Conserved Homologue of the Human Niemann-Pick Disease Type C 2 Protein, hNPC2{dagger}

Adam C. Berger,1,2,3 Thomas H. Vanderford,4,5 Kim M. Gernert,6 J. Wylie Nichols,7 Victor Faundez,2 and Anita H. Corbett1*

Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322,1 Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322,4 BIMCORE (Biomolecular Computing Resource), Emory University, Atlanta, Georgia 30322,6 Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322,7 Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322,2 Graduate Program in Biochemistry, Cell, and Developmental Biology,3 Graduate Program in Population Biology, Ecology, and Evolution, Emory University, Atlanta, Georgia 303225

Received 14 March 2005/ Accepted 24 August 2005

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.

* Corresponding author. Mailing address: Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Rd., NE, Atlanta, GA 30322. Phone: (404) 727-4546. Fax: (404) 727-2738. E-mail: acorbe2{at}emory.edu.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

Eukaryotic Cell, November 2005, p. 1851-1862, Vol. 4, No. 11
1535-9778/05/$08.00+0     doi:10.1128/EC.4.11.1851-1862.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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