Advertisement

Molecular dynamics simulation of PNPLA3 I148M polymorphism reveals reduced substrate access to the catalytic cavity

Authors

  • Yong-Ning Xin,

    1. College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, Shandong Province, China
    2. Qingdao Municipal Hospital, Qingdao 266021, Shandong Province, China
    Search for more papers by this author
    • Yong-Ning Xin, Yuqi Zhao, and Zhong-Hua Lin contributed equally to this work.

  • Yuqi Zhao,

    1. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
    Search for more papers by this author
    • Yong-Ning Xin, Yuqi Zhao, and Zhong-Hua Lin contributed equally to this work.

  • Zhong-Hua Lin,

    1. Qingdao Municipal Hospital, Qingdao 266021, Shandong Province, China
    Search for more papers by this author
    • Yong-Ning Xin, Yuqi Zhao, and Zhong-Hua Lin contributed equally to this work.

  • Xiangjun Jiang,

    1. Qingdao Municipal Hospital, Qingdao 266021, Shandong Province, China
    Search for more papers by this author
  • Shi-Ying Xuan,

    Corresponding author
    1. College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, Shandong Province, China
    2. Qingdao Municipal Hospital, Qingdao 266021, Shandong Province, China
    • Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266021, Shandong Province, China
    Search for more papers by this author
  • Jingfei Huang

    Corresponding author
    1. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
    2. Kunming Institute of Zoology-Chinese University of Hongkong Joint Research Center for Bio-resources and Human Disease Mechanisms, Kunming 650223, China
    • State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32, Eastern Jiaochang Road, Kunming, Yunnan 650223, China
    Search for more papers by this author

  • Author Contributions: Yong-Ning Xin, Yuqi Zhao and Zhong-Hua Lin conceived, designed, and performed the experiments. Xiangjun Jiang analyzed the results and revised the manuscript. Shi-Ying Xuan and Jingfei Huang supervised the work and wrote the manuscript with support from all authors.

Abstract

A missense mutation I148M in PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is significantly correlated with nonalcoholic fatty liver disease (NAFLD). To glean insights into mutation's effect on enzymatic activity, we performed molecular dynamics simulation and flexible docking studies. Our data show that the size of the substrate-access entry site is significantly reduced in mutants, which limits the access of palmitic acid to the catalytic dyad. Besides, the binding free energy calculations suggest low affinity for substrate to mutant enzyme. The substrate-bound system simulations reveal that the spatial arrangement of palmitic acid is distinct in wild-type from that in mutant. The substrate recognition specificity is lost due to the loop where the I148M mutation was located. Our results provide strong evidence for the mechanism by which I148M affects the enzyme activity and suggest that mediating the dynamics may offer a potential avenue for NAFLD. Proteins 2013. © 2012 Wiley Periodicals, Inc.

Ancillary