The structure and function of the Niemann-Pick C1 protein

Niemann-Pick C (NPC) disease is a recessive cholesterol storage disorder ch aracterized by severe, progressive neurodegeneration. The primary causative gene found on chromosome 18q11-12 was identified by a positional cloning a pproach. The NPC1 gene product is predicted to be a large polytopic glycopr otein with a cytoplasmic tail containing a dileucine endosome-targeting mot if. The NPC1 protein sequence shares strong homology with a newly identifie d homologue, NPC1L1, and the morphogen receptor Patched. In addition, a gro up of five NPC1 transmembrane domains share homology with the sterol-sensin g domain of proteins involved in cellular cholesterol homeostasis. Subcellu lar 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. Current ly, there is no direct evidence as to the function of the NPC1 protein; how ever, 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. (C) 2000 Academic Press.