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Title: Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance
Authors: Kabe, Yasuaki
Nakane, Takanori
Koike, Ikko
Yamamoto, Tatsuya
Sugiura, Yuki
Harada, Erisa
Sugase, Kenji  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0001-8623-7743 (unconfirmed)
Shimamura, Tatsuro  kyouindb  KAKEN_id
Ohmura, Mitsuyo
Muraoka, Kazumi
Yamamoto, Ayumi
Uchida, Takeshi
Iwata, So  kyouindb  KAKEN_id
Yamaguchi, Yuki
Krayukhina, Elena
Noda, Masanori
Handa, Hiroshi
Ishimori, Koichiro
Uchiyama, Susumu
Kobayashi, Takuya
Suematsu, Makoto
Author's alias: 小林, 拓也
島村, 達郎
Keywords: Biological sciences
Biochemistry
Cancer
Issue Date: 18-Mar-2016
Publisher: Nature Publishing Group
Journal title: Nature Communications
Volume: 7
Thesis number: 11030
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.
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
URI: http://hdl.handle.net/2433/210220
DOI(Published Version): 10.1038/ncomms11030
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