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Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance

Author

Listed:
  • Yasuaki Kabe

    (Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST))

  • Takanori Nakane

    (Graduate School of Medicine, Kyoto University
    Graduate School of Medicine, Kyoto University)

  • Ikko Koike

    (Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST))

  • Tatsuya Yamamoto

    (Bioorganic Research Institute, Suntory Foundation for Life Sciences)

  • Yuki Sugiura

    (Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST))

  • Erisa Harada

    (Bioorganic Research Institute, Suntory Foundation for Life Sciences)

  • Kenji Sugase

    (Bioorganic Research Institute, Suntory Foundation for Life Sciences)

  • Tatsuro Shimamura

    (Graduate School of Medicine, Kyoto University)

  • Mitsuyo Ohmura

    (Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST))

  • Kazumi Muraoka

    (Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST))

  • Ayumi Yamamoto

    (Faculty of Science, Hokkaido University)

  • Takeshi Uchida

    (Faculty of Science, Hokkaido University)

  • So Iwata

    (Graduate School of Medicine, Kyoto University
    JST, Research Acceleration Program, Membrane Protein Crystallography Project)

  • Yuki Yamaguchi

    (Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology)

  • Elena Krayukhina

    (Graduate School of Engineering, Osaka University)

  • Masanori Noda

    (Graduate School of Engineering, Osaka University)

  • Hiroshi Handa

    (Tokyo Medical University)

  • Koichiro Ishimori

    (Faculty of Science, Hokkaido University)

  • Susumu Uchiyama

    (Graduate School of Engineering, Osaka University
    Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences)

  • Takuya Kobayashi

    (Graduate School of Medicine, Kyoto University
    JST, CREST
    Platform for Drug Discovery, Informatics, and Structural Life Science, JST)

  • Makoto Suematsu

    (Keio University School of Medicine, JST, Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project)

Abstract

Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown. Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules. The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization. Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem. Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells. This study demonstrates protein dimerization via haem–haem stacking, which has not been seen in eukaryotes, and provides insights into its functional significance in cancer.

Suggested Citation

  • Yasuaki Kabe & Takanori Nakane & Ikko Koike & Tatsuya Yamamoto & Yuki Sugiura & Erisa Harada & Kenji Sugase & Tatsuro Shimamura & Mitsuyo Ohmura & Kazumi Muraoka & Ayumi Yamamoto & Takeshi Uchida & So, 2016. "Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11030
    DOI: 10.1038/ncomms11030
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    Cited by:

    1. Yu-Jie Chen & Jeffrey Knupp & Anoop Arunagiri & Leena Haataja & Peter Arvan & Billy Tsai, 2021. "PGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Meeli Mullari & Nicolas Fossat & Niels H. Skotte & Andrea Asenjo-Martinez & David T. Humphreys & Jens Bukh & Agnete Kirkeby & Troels K. H. Scheel & Michael L. Nielsen, 2023. "Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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