Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption

Tao Long, Yang Liu, Yu Qin, Russell A. DeBose-Boyd, Xiaochun Li

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Polytopic Niemann-Pick C1-like 1 (NPC1L1) plays a major role in intestinal absorption of biliary cholesterol, vitamin E (VE), and vitamin K (VK). The drug ezetimibe inhibits NPC1L1-mediated absorption of cholesterol, lowering of circulating levels of low-density lipoprotein cholesterol. Here, we report cryo-electron microscopy structures of human NPC1L1 (hNPC1L1) bound to either cholesterol or a lipid resembling VE. These findings, together with functional assays, reveal that the same intramolecular channel in hNPC1L1 mediates transport of VE and cholesterol. hNPC1L1 exists primarily as a homodimer; dimerization is mediated by aromatic residues within a region of transmembrane helix 2 that exhibits a horizonal orientation in the membrane. Mutation of tryptophan-347 lies in this region disrupts dimerization and the resultant monomeric NPC1L1 exhibits reduced efficiency of cholesterol uptake. These findings identify the oligomeric state of hNPC1L1 as a target for therapies that inhibit uptake of dietary cholesterol and reduce the incidence of cardiovascular disease.

Original languageEnglish (US)
Article numbereabh3997
JournalScience Advances
Volume7
Issue number34
DOIs
StatePublished - Aug 2021

ASJC Scopus subject areas

  • General

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