Structure of human Niemann-Pick C1 protein.
Niemann-Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann-Pick disease type C, and Ebola virus infection. NPC1 contains 13 transmembrane segments (TMs), five of which are thought to represent a "sterol-sensing domain" (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2-13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1's SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. We propose a model for NPC1 function in cholesterol sensing and transport.
['Li|Xiaochun|X|', 'Wang|Jiawei|J|', 'Coutavas|Elias|E|', 'Shi|Hang|H|', 'Hao|Qi|Q|', 'Blobel|Günter|G|']
D000595:Amino Acid Sequence D002352:Carrier Proteins D002784:Cholesterol D018076:DNA, Complementary D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D008247:Lysosomes D008562:Membrane Glycoproteins D000077296:Niemann-Pick C1 Protein D011487:Protein Conformation D016415:Sequence Alignment
sterol-sensing domain crystal structure allostery cholesterol traffic endosomal membrane