The NPC1 protein: structure implies function

Niemann-Pick type C (NPC) is a lysosomal storage disorder, characterized by intracellular accumulation of low-density lipoprotein (LDL)-derived cholesterol and neurodegeneration leading to premature death. The most common form of the disease, NPCl, results from mutations in the NPCl gene. Thus, the NPCl protein is the focus of intense investigation to elucidate the function of this protein and its role in the disease pathogenesis. Recent studies have revealed the NPCl subcellular location, topology and potential functions of the NPCl protein. In lieu of direct experimental evidence, certain hypotheses about the function of NPCl can be inferred by analyzing disease-causing mutations, NPCl protein sequence homology to other related proteins, and the potential tertiary structure similarity between NPCl and its prokaryotic ancestors, such as the E. coli RND permease AcrB. This review will discuss recent work on the characterization and function of the NPCl protein and highlight structural features that may be important in assisting in the elucidation of NPCl function and role in subcellular lipid transport and homeostasis. (C) 2004 Elsevier B.V All rights reserved.