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Title: Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol

Abstract

LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3{beta}-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3{beta}-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from the binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.

Authors:
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  1. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006175
Resource Type:
Journal Article
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 137; Journal Issue: (7) ; 06, 2009; Journal ID: ISSN 0092-8674
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CHAINS; CHOLESTEROL; ESTERS; GENE MUTATIONS; HYDROLYSIS; LYSOSOMES; MEMBRANES; OPENINGS; ORIENTATION; PROTEINS

Citation Formats

Kwon, Hyock Joo, Abi-Mosleh, Lina, Wang, Michael L., Deisenhofer, Johann, Goldstein, Joseph L., Brown, Michael S., Infante, Rodney E., and UTSMC). Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol. United States: N. p., 2010. Web. doi:10.1016/j.cell.2009.03.049.
Kwon, Hyock Joo, Abi-Mosleh, Lina, Wang, Michael L., Deisenhofer, Johann, Goldstein, Joseph L., Brown, Michael S., Infante, Rodney E., & UTSMC). Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol. United States. doi:10.1016/j.cell.2009.03.049.
Kwon, Hyock Joo, Abi-Mosleh, Lina, Wang, Michael L., Deisenhofer, Johann, Goldstein, Joseph L., Brown, Michael S., Infante, Rodney E., and UTSMC). Tue . "Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol". United States. doi:10.1016/j.cell.2009.03.049.
@article{osti_1006175,
title = {Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol},
author = {Kwon, Hyock Joo and Abi-Mosleh, Lina and Wang, Michael L. and Deisenhofer, Johann and Goldstein, Joseph L. and Brown, Michael S. and Infante, Rodney E. and UTSMC)},
abstractNote = {LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3{beta}-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3{beta}-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from the binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.},
doi = {10.1016/j.cell.2009.03.049},
journal = {Cell},
issn = {0092-8674},
number = (7) ; 06, 2009,
volume = 137,
place = {United States},
year = {2010},
month = {9}
}