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

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 Iwata, Yuki Yamaguchi, Elena Krayukhina, Masanori Noda, Hiroshi Handa, Koichiro Ishimori, Susumu Uchiyama, Takuya Kobayashi () and Makoto Suematsu ()
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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
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
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
Takuya Kobayashi: Graduate School of Medicine, Kyoto University
Makoto Suematsu: Keio University School of Medicine, JST, Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11030

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