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 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.
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Tokyo 160-8582, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
authors.affiliation: Department of Medical Chemistry and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.|Department of Statistical Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Nakane
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Tokyo 160-8582, Japan.
authors.forename: Ikko
authors.initials: I
authors.lastname: Koike
authors.affiliation: Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto 619-0284, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Tokyo 160-8582, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugiura
authors.affiliation: Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto 619-0284, Japan.
authors.forename: Erisa
authors.initials: E
authors.lastname: Harada
authors.affiliation: Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto 619-0284, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugase
authors.affiliation: Department of Medical Chemistry and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Tokyo 160-8582, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Ohmura
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, and Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Tokyo 160-8582, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Muraoka
authors.affiliation: Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Medical Chemistry and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.|JST, Research Acceleration Program, Membrane Protein Crystallography Project, Kyoto 606-8501, Japan.
authors.forename: So
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan.
authors.forename: Elena
authors.initials: E
authors.lastname: Krayukhina
authors.affiliation: Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Noda
authors.affiliation: Department of Nanoparticle Translational Research, Tokyo Medical University, Tokyo 160-8402, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
authors.affiliation: Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Koichiro
authors.identifier: http://orcid.org/0000-0002-5868-0462
authors.initials: K
authors.lastname: Ishimori
authors.affiliation: Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan.|Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Uchiyama
authors.affiliation: Department of Medical Chemistry and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.|JST, CREST, Kyoto 606-8501, Japan.|Platform for Drug Discovery, Informatics, and Structural Life Science, JST, Kyoto 606-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, JST, Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo 160-8582, Japan.
authors.forename: Makoto
authors.identifier: http://orcid.org/0000-0002-7165-6336
authors.initials: M
authors.lastname: Suematsu
mesh_terms: D002248:Carbon Monoxide / Q000378:metabolism; D049109:Cell Proliferation; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D055503:Protein Multimerization; D011980:Receptors, Progesterone / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012996:Solutions
chemical_list: D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D011980:Receptors, Progesterone; D017480:Receptors, sigma; D012996:Solutions; C106107:sigma-2 receptor; D006418:Heme; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D066246:ErbB Receptors