Crystal structure of a lipin/Pah phosphatidic acid phosphatase

Valerie I. Khayyo, Reece M. Hoffmann, Huan Wang, Justin A. Bell, John E. Burke, Karen Reue and Michael V. Airola ()
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Valerie I. Khayyo: Stony Brook University
Reece M. Hoffmann: University of Victoria
Huan Wang: David Geffen School of Medicine at UCLA
Justin A. Bell: Stony Brook University
John E. Burke: University of Victoria
Karen Reue: David Geffen School of Medicine at UCLA
Michael V. Airola: Stony Brook University

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15124-z

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