The structure and function of the Niemann-Pick C1 protein.
Niemann-Pick C (NPC) disease is a recessive cholesterol storage disorder characterized by severe, progressive neurodegeneration. The primary causative gene found on chromosome 18q11-12 was identified by a positional cloning approach. The NPC1 gene product is predicted to be a large polytopic glycoprotein with a cytoplasmic tail containing a dileucine endosome-targeting motif. The NPC1 protein sequence shares strong homology with a newly identified homologue, NPC1L1, and the morphogen receptor Patched. In addition, a group of five NPC1 transmembrane domains share homology with the sterol-sensing domain of proteins involved in cellular cholesterol homeostasis. Subcellular localization studies have shown NPC1 to reside in late endosomes and to transiently associate with lysosomes and the trans-Golgi network. Analysis of its topological arrangement in membranes suggests that NPC1 contains 13 transmembrane domains and three large, hydrophilic, lumenal loops. Currently, there is no direct evidence as to the function of the NPC1 protein; however, a number of observations suggest that NPC1 may be related to a family of prokaryotic efflux pumps and thus it may also act as a molecular pump.
Ioannou
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Department of Human Genetics, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA. ioanny01@doc.mssm.edu
D000595:Amino Acid Sequence; D001693:Biological Transport, Active; D002352:Carrier Proteins; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011506:Proteins; D002784:Cholesterol