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TitleStructures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption.
Journal, issue, pagesSci Adv, Vol. 7, Issue 34, Year 2021
Publish dateAug 18, 2021
AuthorsTao Long / Yang Liu / Yu Qin / Russell A DeBose-Boyd / Xiaochun Li /
PubMed AbstractPolytopic 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 ...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.
External linksSci Adv / PubMed:34407950 / PubMed Central
MethodsEM (single particle)
Resolution3.33 - 3.58 Å
Structure data

24178

7n4u

EMDB-24178, PDB-7n4u:
Structure of human NPC1L1
Method: EM (single particle) / Resolution: 3.34 Å

24179

7n4v

EMDB-24179, PDB-7n4v:
Structure of cholesterol-bound human NPC1L1
Method: EM (single particle) / Resolution: 3.58 Å

24180

7n4x

EMDB-24180, PDB-7n4x:
Structure of human NPC1L1 mutant-W347R
Method: EM (single particle) / Resolution: 3.33 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-VIV:
(2R)-2,5,7,8-TETRAMETHYL-2-[(4R,8R)-4,8,12-TRIMETHYLTRIDECYL]CHROMAN-6-OL / Α-Tocopherol

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Transporter

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