Journal Article 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

72016-03-18 , Nature Publishing Group
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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