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Title: Lipid bilayer thickness determines cholesterol's location in model membranes

Cholesterol is an essential biomolecule of animal cell membranes, and an important precursor for the biosynthesis of certain hormones and vitamins. It is also thought to play a key role in cell signaling processes associated with functional plasma membrane microdomains (domains enriched in cholesterol), commonly referred to as rafts. In all of these diverse biological phenomena, the transverse location of cholesterol in the membrane is almost certainly an important structural feature. Using a combination of neutron scattering and solid-state 2H NMR, we have determined the location and orientation of cholesterol in phosphatidylcholine (PC) model membranes having fatty acids of different lengths and degrees of unsaturation. The data establish that cholesterol reorients rapidly about the bilayer normal in all the membranes studied, but is tilted and forced to span the bilayer midplane in the very thin bilayers. The possibility that cholesterol lies flat in the middle of bilayers, including those made from PC lipids containing polyunsaturated fatty acids (PUFAs), is ruled out. Finally, these results support the notion that hydrophobic thickness is the primary determinant of cholesterol's location in membranes.
Authors:
 [1] ;  [2] ;  [3] ;  [3] ;  [4] ;  [5] ;  [5] ;  [6] ;  [6] ;  [6] ;  [7]
  1. Brock Univ., St. Catharines (Canada); Univ. of Graz, Graz (Austria)
  2. Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. Univ. of Arkansas, Fayetteville, AR (United States)
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
  5. Brock Univ., St. Catharines (Canada)
  6. Indiana Univ. - Purdue Univ. Indianapolis, Indianapolis, IN (United States)
  7. Brock Univ., St. Catharines (Canada); Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Indiana Univ. - Purdue Univ. Indianapolis, Indianapolis, IN (United States)
Publication Date:
Grant/Contract Number:
AC05-00OR22725
Type:
Accepted Manuscript
Journal Name:
Soft Matter
Additional Journal Information:
Journal Volume: 12; Journal Issue: 47; Journal ID: ISSN 1744-683X
Publisher:
Royal Society of Chemistry
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; cholesterol; PUFA; neutron scattering; MD simulations; solid state 2H NMR
OSTI Identifier:
1344271

Marquardt, Drew, Heberle, Frederick A., Greathouse, Denise V., Koeppe, II, Roger E., Standaert, Robert F., Van Oosten, Brad J., Harroun, Thad A., Kinnun, Jacob J., Williams, Justin A., Wassall, Stephen R., and Katsaras, John. Lipid bilayer thickness determines cholesterol's location in model membranes. United States: N. p., Web. doi:10.1039/C6SM01777K.
Marquardt, Drew, Heberle, Frederick A., Greathouse, Denise V., Koeppe, II, Roger E., Standaert, Robert F., Van Oosten, Brad J., Harroun, Thad A., Kinnun, Jacob J., Williams, Justin A., Wassall, Stephen R., & Katsaras, John. Lipid bilayer thickness determines cholesterol's location in model membranes. United States. doi:10.1039/C6SM01777K.
Marquardt, Drew, Heberle, Frederick A., Greathouse, Denise V., Koeppe, II, Roger E., Standaert, Robert F., Van Oosten, Brad J., Harroun, Thad A., Kinnun, Jacob J., Williams, Justin A., Wassall, Stephen R., and Katsaras, John. 2016. "Lipid bilayer thickness determines cholesterol's location in model membranes". United States. doi:10.1039/C6SM01777K. https://www.osti.gov/servlets/purl/1344271.
@article{osti_1344271,
title = {Lipid bilayer thickness determines cholesterol's location in model membranes},
author = {Marquardt, Drew and Heberle, Frederick A. and Greathouse, Denise V. and Koeppe, II, Roger E. and Standaert, Robert F. and Van Oosten, Brad J. and Harroun, Thad A. and Kinnun, Jacob J. and Williams, Justin A. and Wassall, Stephen R. and Katsaras, John},
abstractNote = {Cholesterol is an essential biomolecule of animal cell membranes, and an important precursor for the biosynthesis of certain hormones and vitamins. It is also thought to play a key role in cell signaling processes associated with functional plasma membrane microdomains (domains enriched in cholesterol), commonly referred to as rafts. In all of these diverse biological phenomena, the transverse location of cholesterol in the membrane is almost certainly an important structural feature. Using a combination of neutron scattering and solid-state 2H NMR, we have determined the location and orientation of cholesterol in phosphatidylcholine (PC) model membranes having fatty acids of different lengths and degrees of unsaturation. The data establish that cholesterol reorients rapidly about the bilayer normal in all the membranes studied, but is tilted and forced to span the bilayer midplane in the very thin bilayers. The possibility that cholesterol lies flat in the middle of bilayers, including those made from PC lipids containing polyunsaturated fatty acids (PUFAs), is ruled out. Finally, these results support the notion that hydrophobic thickness is the primary determinant of cholesterol's location in membranes.},
doi = {10.1039/C6SM01777K},
journal = {Soft Matter},
number = 47,
volume = 12,
place = {United States},
year = {2016},
month = {10}
}