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

• DOI: 10.1038/ncomms11030
• Publication Date: 2016-03-18T11:27:07Z
• Authors: 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
• Keywords: 0301 basic medicine; Science; Heme; Crystallography, X-Ray; Biochemistry; Models, Biological; Article; 03 medical and health sciences; Cytochrome P-450 Enzyme System; Neoplasms; Humans; Receptors, sigma; Cancer; Cell Proliferation; Carbon Monoxide; Q; Membrane Proteins; 3. Good health; ErbB Receptors; Solutions; Biological sciences; Drug Resistance, Neoplasm; Protein Multimerization; Receptors, Progesterone; Protein Binding; Signal Transduction

AbstractProgesterone-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.