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Title: Crystal structure of a lipin/Pah phosphatidic acid phosphatase

Abstract

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.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [3]; ORCiD logo [1]; ORCiD logo [2];  [3]; ORCiD logo [1]
  1. Stony Brook Univ., NY (United States)
  2. Univ. of Victoria, BC (Canada)
  3. Univ. of California, Los Angeles, CA (United States). David Geffen School of Medicine
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); National Science Foundation (NSF); American Heart Association (AHA); Natural Sciences and Engineering Research Council of Canada (NSERC); Canadian Institutes of Health Research (CIHR); Michael Smith Foundation for Health Research
OSTI Identifier:
1605448
Grant/Contract Number:  
S10OD025017; CHE-0722519; R35 GM128666; P01 HL090553; P01 HL028481; 17SDG33410860; 19PRE34450192; 18POST34060200; NSERC-2014-05218; 17686
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Hydrolases; Mass spectrometry; Membrane lipids; Membrane proteins; X-ray crystallography

Citation Formats

Khayyo, Valerie I., Hoffmann, Reece M., Wang, Huan, Bell, Justin A., Burke, John E., Reue, Karen, and Airola, Michael V. Crystal structure of a lipin/Pah phosphatidic acid phosphatase. United States: N. p., 2020. Web. doi:10.1038/s41467-020-15124-z.
Khayyo, Valerie I., Hoffmann, Reece M., Wang, Huan, Bell, Justin A., Burke, John E., Reue, Karen, & Airola, Michael V. Crystal structure of a lipin/Pah phosphatidic acid phosphatase. United States. doi:https://doi.org/10.1038/s41467-020-15124-z
Khayyo, Valerie I., Hoffmann, Reece M., Wang, Huan, Bell, Justin A., Burke, John E., Reue, Karen, and Airola, Michael V. Wed . "Crystal structure of a lipin/Pah phosphatidic acid phosphatase". United States. doi:https://doi.org/10.1038/s41467-020-15124-z. https://www.osti.gov/servlets/purl/1605448.
@article{osti_1605448,
title = {Crystal structure of a lipin/Pah phosphatidic acid phosphatase},
author = {Khayyo, Valerie I. and Hoffmann, Reece M. and Wang, Huan and Bell, Justin A. and Burke, John E. and Reue, Karen and Airola, Michael V.},
abstractNote = {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.},
doi = {10.1038/s41467-020-15124-z},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {3}
}

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