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.
Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065; blobel@rockefeller.edu xli05@rockefeller.edu.
Xiaochun
X
Li
State Key Laboratory of Membrane Biology, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Jiawei
J
Wang
Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
Elias
E
Coutavas
Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
Hang
H
Shi
Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
Qi
Q
Hao
Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065; blobel@rockefeller.edu xli05@rockefeller.edu.
Günter
G
Blobel
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D011487:Protein Conformation; D016415:Sequence Alignment
D002352:Carrier Proteins; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D002784:Cholesterol
allostery; cholesterol traffic; crystal structure; endosomal membrane; sterol-sensing domain