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Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles

Lecithin:cholesterol acyltransferase (LCAT) catalyzes a critical step of reverse cholesterol transport by esterifying cholesterol in high density lipoprotein (HDL) particles. LCAT is activated by apolipoprotein A-I (ApoA-I), which forms a double belt around HDL, however the manner in which LCAT enga...

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Autores principales: Manthei, Kelly A., Patra, Dhabaleswar, Wilson, Christopher J., Fawaz, Maria V., Piersimoni, Lolita, Shenkar, Jenny Capua, Yuan, Wenmin, Andrews, Philip C., Engen, John R., Schwendeman, Anna, Ohi, Melanie D., Tesmer, John J. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962161/
https://www.ncbi.nlm.nih.gov/pubmed/31942029
http://dx.doi.org/10.1038/s42003-019-0749-z
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author Manthei, Kelly A.
Patra, Dhabaleswar
Wilson, Christopher J.
Fawaz, Maria V.
Piersimoni, Lolita
Shenkar, Jenny Capua
Yuan, Wenmin
Andrews, Philip C.
Engen, John R.
Schwendeman, Anna
Ohi, Melanie D.
Tesmer, John J. G.
author_facet Manthei, Kelly A.
Patra, Dhabaleswar
Wilson, Christopher J.
Fawaz, Maria V.
Piersimoni, Lolita
Shenkar, Jenny Capua
Yuan, Wenmin
Andrews, Philip C.
Engen, John R.
Schwendeman, Anna
Ohi, Melanie D.
Tesmer, John J. G.
author_sort Manthei, Kelly A.
collection PubMed
description Lecithin:cholesterol acyltransferase (LCAT) catalyzes a critical step of reverse cholesterol transport by esterifying cholesterol in high density lipoprotein (HDL) particles. LCAT is activated by apolipoprotein A-I (ApoA-I), which forms a double belt around HDL, however the manner in which LCAT engages its lipidic substrates and ApoA-I in HDL is poorly understood. Here, we used negative stain electron microscopy, crosslinking, and hydrogen-deuterium exchange studies to refine the molecular details of the LCAT–HDL complex. Our data are consistent with LCAT preferentially binding to the edge of discoidal HDL near the boundary between helix 5 and 6 of ApoA-I in a manner that creates a path from the lipid bilayer to the active site of LCAT. Our results provide not only an explanation why LCAT activity diminishes as HDL particles mature, but also direct support for the anti-parallel double belt model of HDL, with LCAT binding preferentially to the helix 4/6 region.
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spelling pubmed-69621612020-01-22 Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles Manthei, Kelly A. Patra, Dhabaleswar Wilson, Christopher J. Fawaz, Maria V. Piersimoni, Lolita Shenkar, Jenny Capua Yuan, Wenmin Andrews, Philip C. Engen, John R. Schwendeman, Anna Ohi, Melanie D. Tesmer, John J. G. Commun Biol Article Lecithin:cholesterol acyltransferase (LCAT) catalyzes a critical step of reverse cholesterol transport by esterifying cholesterol in high density lipoprotein (HDL) particles. LCAT is activated by apolipoprotein A-I (ApoA-I), which forms a double belt around HDL, however the manner in which LCAT engages its lipidic substrates and ApoA-I in HDL is poorly understood. Here, we used negative stain electron microscopy, crosslinking, and hydrogen-deuterium exchange studies to refine the molecular details of the LCAT–HDL complex. Our data are consistent with LCAT preferentially binding to the edge of discoidal HDL near the boundary between helix 5 and 6 of ApoA-I in a manner that creates a path from the lipid bilayer to the active site of LCAT. Our results provide not only an explanation why LCAT activity diminishes as HDL particles mature, but also direct support for the anti-parallel double belt model of HDL, with LCAT binding preferentially to the helix 4/6 region. Nature Publishing Group UK 2020-01-15 /pmc/articles/PMC6962161/ /pubmed/31942029 http://dx.doi.org/10.1038/s42003-019-0749-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Manthei, Kelly A.
Patra, Dhabaleswar
Wilson, Christopher J.
Fawaz, Maria V.
Piersimoni, Lolita
Shenkar, Jenny Capua
Yuan, Wenmin
Andrews, Philip C.
Engen, John R.
Schwendeman, Anna
Ohi, Melanie D.
Tesmer, John J. G.
Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles
title Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles
title_full Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles
title_fullStr Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles
title_full_unstemmed Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles
title_short Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles
title_sort structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962161/
https://www.ncbi.nlm.nih.gov/pubmed/31942029
http://dx.doi.org/10.1038/s42003-019-0749-z
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