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

Kabe, Yasuaki, Nakane, Takanori, Koike, Ikko, Yamamoto, Tatsuya, Sugiura, Yuki, Harada, Erisa, Sugase, Kenji, Shimamura, Tatsuro, Ohmura, Mitsuyo, Muraoka, Kazumi, Yamamoto, Ayumi, Uchida, Takeshi, Iwata, So, Yamaguchi, Yuki, Krayukhina, Elena, Noda, Masanori, Handa, Hiroshi, Ishimori, Koichiro, Uchiyama, Susumu, Kobayashi, Takuya, Suematsu, Makoto·2016·Nature Communications
DOI 10.1038/ncomms11030PMC PMC4802085
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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.

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Metadata

Authors
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.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-03-18
Volume
7
Issue
1
ISSN
2041-1723
DOI
10.1038/ncomms11030
PMC
PMC4802085
Cited by
171
References
4
Language
en
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