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Crystal structure of a lipin/Pah phosphatidic acid phosphatase
Lipin/Pah phosphatidic acid phosphatases (PAPs) generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Inactivating mutations cause rhabdomyolysis, autoinflammatory disease, and aberrant fat storage. Disease-mutations cluster within the conserved N-Lip and C-Lip regions t...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066176/ https://www.ncbi.nlm.nih.gov/pubmed/32161260 http://dx.doi.org/10.1038/s41467-020-15124-z |
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author | Khayyo, Valerie I. Hoffmann, Reece M. Wang, Huan Bell, Justin A. Burke, John E. Reue, Karen Airola, Michael V. V. |
author_facet | Khayyo, Valerie I. Hoffmann, Reece M. Wang, Huan Bell, Justin A. Burke, John E. Reue, Karen Airola, Michael V. V. |
author_sort | Khayyo, Valerie I. |
collection | PubMed |
description | Lipin/Pah phosphatidic acid phosphatases (PAPs) generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Inactivating mutations cause rhabdomyolysis, autoinflammatory disease, and aberrant fat storage. Disease-mutations cluster within the conserved N-Lip and C-Lip regions that are separated by 500-residues in humans. To understand how the N-Lip and C-Lip combine for PAP function, we determined crystal structures of Tetrahymena thermophila Pah2 (Tt Pah2) that directly fuses the N-Lip and C-Lip. Tt Pah2 adopts a two-domain architecture where the N-Lip combines with part of the C-Lip to form an immunoglobulin-like domain and the remaining C-Lip forms a HAD-like catalytic domain. An N-Lip C-Lip fusion of mouse lipin-2 is catalytically active, which suggests mammalian lipins function with the same domain architecture as Tt Pah2. HDX-MS identifies an N-terminal amphipathic helix essential for membrane association. Disease-mutations disrupt catalysis or destabilize the protein fold. This illustrates mechanisms for lipin/Pah PAP function, membrane association, and lipin-related pathologies. |
format | Online Article Text |
id | pubmed-7066176 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70661762020-03-18 Crystal structure of a lipin/Pah phosphatidic acid phosphatase Khayyo, Valerie I. Hoffmann, Reece M. Wang, Huan Bell, Justin A. Burke, John E. Reue, Karen Airola, Michael V. V. Nat Commun Article Lipin/Pah phosphatidic acid phosphatases (PAPs) generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Inactivating mutations cause rhabdomyolysis, autoinflammatory disease, and aberrant fat storage. Disease-mutations cluster within the conserved N-Lip and C-Lip regions that are separated by 500-residues in humans. To understand how the N-Lip and C-Lip combine for PAP function, we determined crystal structures of Tetrahymena thermophila Pah2 (Tt Pah2) that directly fuses the N-Lip and C-Lip. Tt Pah2 adopts a two-domain architecture where the N-Lip combines with part of the C-Lip to form an immunoglobulin-like domain and the remaining C-Lip forms a HAD-like catalytic domain. An N-Lip C-Lip fusion of mouse lipin-2 is catalytically active, which suggests mammalian lipins function with the same domain architecture as Tt Pah2. HDX-MS identifies an N-terminal amphipathic helix essential for membrane association. Disease-mutations disrupt catalysis or destabilize the protein fold. This illustrates mechanisms for lipin/Pah PAP function, membrane association, and lipin-related pathologies. Nature Publishing Group UK 2020-03-11 /pmc/articles/PMC7066176/ /pubmed/32161260 http://dx.doi.org/10.1038/s41467-020-15124-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 Khayyo, Valerie I. Hoffmann, Reece M. Wang, Huan Bell, Justin A. Burke, John E. Reue, Karen Airola, Michael V. V. Crystal structure of a lipin/Pah phosphatidic acid phosphatase |
title | Crystal structure of a lipin/Pah phosphatidic acid phosphatase |
title_full | Crystal structure of a lipin/Pah phosphatidic acid phosphatase |
title_fullStr | Crystal structure of a lipin/Pah phosphatidic acid phosphatase |
title_full_unstemmed | Crystal structure of a lipin/Pah phosphatidic acid phosphatase |
title_short | Crystal structure of a lipin/Pah phosphatidic acid phosphatase |
title_sort | crystal structure of a lipin/pah phosphatidic acid phosphatase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066176/ https://www.ncbi.nlm.nih.gov/pubmed/32161260 http://dx.doi.org/10.1038/s41467-020-15124-z |
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