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Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis
Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358717/ https://www.ncbi.nlm.nih.gov/pubmed/30559189 http://dx.doi.org/10.1073/pnas.1817984116 |
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author | Birrane, Gabriel Beigneux, Anne P. Dwyer, Brian Strack-Logue, Bettina Kristensen, Kristian Kølby Francone, Omar L. Fong, Loren G. Mertens, Haydyn D. T. Pan, Clark Q. Ploug, Michael Young, Stephen G. Meiyappan, Muthuraman |
author_facet | Birrane, Gabriel Beigneux, Anne P. Dwyer, Brian Strack-Logue, Bettina Kristensen, Kristian Kølby Francone, Omar L. Fong, Loren G. Mertens, Haydyn D. T. Pan, Clark Q. Ploug, Michael Young, Stephen G. Meiyappan, Muthuraman |
author_sort | Birrane, Gabriel |
collection | PubMed |
description | Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1’s acidic domain preserves LPL structure and activity, we crystallized an LPL–GPIHBP1 complex and solved its structure. GPIHBP1’s LU domain binds to LPL’s C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1’s acidic domain was not defined in the electron density map but was positioned to interact with LPL’s large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL–GPIHBP1 structure provides insights into mutations causing chylomicronemia. |
format | Online Article Text |
id | pubmed-6358717 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-63587172019-02-05 Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis Birrane, Gabriel Beigneux, Anne P. Dwyer, Brian Strack-Logue, Bettina Kristensen, Kristian Kølby Francone, Omar L. Fong, Loren G. Mertens, Haydyn D. T. Pan, Clark Q. Ploug, Michael Young, Stephen G. Meiyappan, Muthuraman Proc Natl Acad Sci U S A PNAS Plus Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1’s acidic domain preserves LPL structure and activity, we crystallized an LPL–GPIHBP1 complex and solved its structure. GPIHBP1’s LU domain binds to LPL’s C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1’s acidic domain was not defined in the electron density map but was positioned to interact with LPL’s large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL–GPIHBP1 structure provides insights into mutations causing chylomicronemia. National Academy of Sciences 2019-01-29 2018-12-17 /pmc/articles/PMC6358717/ /pubmed/30559189 http://dx.doi.org/10.1073/pnas.1817984116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | PNAS Plus Birrane, Gabriel Beigneux, Anne P. Dwyer, Brian Strack-Logue, Bettina Kristensen, Kristian Kølby Francone, Omar L. Fong, Loren G. Mertens, Haydyn D. T. Pan, Clark Q. Ploug, Michael Young, Stephen G. Meiyappan, Muthuraman Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis |
title | Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis |
title_full | Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis |
title_fullStr | Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis |
title_full_unstemmed | Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis |
title_short | Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis |
title_sort | structure of the lipoprotein lipase–gpihbp1 complex that mediates plasma triglyceride hydrolysis |
topic | PNAS Plus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358717/ https://www.ncbi.nlm.nih.gov/pubmed/30559189 http://dx.doi.org/10.1073/pnas.1817984116 |
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