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Crystal structure of a lipin/Pah phosphatidic acid phosphatase

Author

Listed:
  • 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)

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.

Suggested Citation

  • Valerie I. Khayyo & Reece M. Hoffmann & Huan Wang & Justin A. Bell & John E. Burke & Karen Reue & Michael V. Airola, 2020. "Crystal structure of a lipin/Pah phosphatidic acid phosphatase," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15124-z
    DOI: 10.1038/s41467-020-15124-z
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    Cited by:

    1. Ruyi Fan & Fen Zhao & Zhou Gong & Yanke Chen & Bao Yang & Chen Zhou & Jie Zhang & Zhangmeng Du & Xuemin Wang & Ping Yin & Liang Guo & Zhu Liu, 2023. "Insights into the mechanism of phospholipid hydrolysis by plant non-specific phospholipase C," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Nivea Pereira de Sa & Adam Taouil & Jinwoo Kim & Timothy Clement & Reece M. Hoffmann & John E. Burke & Robert C. Rizzo & Iwao Ojima & Maurizio Del Poeta & Michael V. Airola, 2021. "Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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