Structure of human Niemann–Pick C1 protein

Li, Xiaochun; Wang, Jiawei; Coutavas, Elias; Shi, Hang; Hao, Qi; Blobel, Günter

doi:10.1073/pnas.1607795113

Structure of human Niemann–Pick C1 protein

Journal Article · Wed Jun 15 00:00:00 EDT 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1607795113· OSTI ID:1274750

Li, Xiaochun ^[1]; Wang, Jiawei ^[2]; Coutavas, Elias ^[1]; Shi, Hang ^[1]; Hao, Qi ^[1]; Blobel, Günter ^[1]

Rockefeller Univ., New York, NY (United States)
Tsinghua Univ., Beijing (China)

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. In conclusion, we propose a model for NPC1 function in cholesterol sensing and transport.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Howard Hughes Medical Inst.; Rockefeller Univ.

OSTI ID:: 1274750

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 29 Vol. 113; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
allostery
cholesterol traffic
crystal structure
domain
endosomal membrane
sterol-sensing

Structure of human Niemann–Pick C1 protein

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