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; Makoto Suematsu

doi:10.1038/ncomms11030

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 KobayashiMakoto Suematsu

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133 Citations (Scopus)

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.

Original language	English
Article number	11030
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11030
Publication status	Published - 2016 Mar 18

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms11030

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Kabe, Y., Nakane, T., Koike, I., Yamamoto, T., Sugiura, Y., Harada, E., Sugase, K., Shimamura, T., Ohmura, M., Muraoka, K., Yamamoto, A., Uchida, T., Iwata, S., Yamaguchi, Y., Krayukhina, E., Noda, M., Handa, H., Ishimori, K., Uchiyama, S., ... Suematsu, M. (2016). Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. Nature communications, 7, Article 11030. https://doi.org/10.1038/ncomms11030

Kabe, Y, Nakane, T, Koike, I, Yamamoto, T, Sugiura, Y, Harada, E, Sugase, K, Shimamura, T, Ohmura, M, Muraoka, K, Yamamoto, A, Uchida, T, Iwata, S, Yamaguchi, Y, Krayukhina, E, Noda, M, Handa, H, Ishimori, K, Uchiyama, S, Kobayashi, T & Suematsu, M 2016, 'Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance', Nature communications, vol. 7, 11030. https://doi.org/10.1038/ncomms11030

@article{b0901e3596944727888042ac23471ab2,

title = "Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance",

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 {\AA} 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.",

author = "Yasuaki Kabe and Takanori Nakane and Ikko Koike and Tatsuya Yamamoto and Yuki Sugiura and Erisa Harada and Kenji Sugase and Tatsuro Shimamura and Mitsuyo Ohmura and Kazumi Muraoka and Ayumi Yamamoto and Takeshi Uchida and So Iwata and Yuki Yamaguchi and Elena Krayukhina and Masanori Noda and Hiroshi Handa and Koichiro Ishimori and Susumu Uchiyama and Takuya Kobayashi and Makoto Suematsu",

note = "Funding Information: X-ray crystallographic data was collected at the BL-41XU of SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI) (proposal no. 2011B1229, 2012A1184 and 2012B1253). This work was supported by the Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Suematsu Gas Biology Project (to M.S.). The present affiliation of M.S. is President, Japan Agency for Medical Research and Development (AMED). Mass spectrometry infrastructure in this work was partly supported by AMED-CREST (to Y.K.), and Platform for Drug Discovery, Informatics, and Structural Life Science from the ministry of Education, Culture, Sports, Science and Technology, Japan (T.K.).",

year = "2016",

month = mar,

day = "18",

doi = "10.1038/ncomms11030",

language = "English",

volume = "7",

journal = "Nature communications",

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T1 - Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance

AU - Kabe, Yasuaki

AU - Nakane, Takanori

AU - Koike, Ikko

AU - Yamamoto, Tatsuya

AU - Sugiura, Yuki

AU - Harada, Erisa

AU - Sugase, Kenji

AU - Shimamura, Tatsuro

AU - Ohmura, Mitsuyo

AU - Muraoka, Kazumi

AU - Yamamoto, Ayumi

AU - Uchida, Takeshi

AU - Iwata, So

AU - Yamaguchi, Yuki

AU - Krayukhina, Elena

AU - Noda, Masanori

AU - Handa, Hiroshi

AU - Ishimori, Koichiro

AU - Uchiyama, Susumu

AU - Kobayashi, Takuya

AU - Suematsu, Makoto

N1 - Funding Information: X-ray crystallographic data was collected at the BL-41XU of SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI) (proposal no. 2011B1229, 2012A1184 and 2012B1253). This work was supported by the Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Suematsu Gas Biology Project (to M.S.). The present affiliation of M.S. is President, Japan Agency for Medical Research and Development (AMED). Mass spectrometry infrastructure in this work was partly supported by AMED-CREST (to Y.K.), and Platform for Drug Discovery, Informatics, and Structural Life Science from the ministry of Education, Culture, Sports, Science and Technology, Japan (T.K.).

PY - 2016/3/18

Y1 - 2016/3/18

N2 - 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.

AB - 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.

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DO - 10.1038/ncomms11030

M3 - Article

C2 - 26988023

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SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 11030

ER -

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

Abstract

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