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Nat Commun. 2016 Mar 18;7:11030. doi: 10.1038/ncomms11030.

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

Author information

1
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.
2
Department of Medical Chemistry and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
3
Department of Statistical Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
4
Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto 619-0284, Japan.
5
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
6
JST, Research Acceleration Program, Membrane Protein Crystallography Project, Kyoto 606-8501, Japan.
7
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
8
Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan.
9
Department of Nanoparticle Translational Research, Tokyo Medical University, Tokyo 160-8402, Japan.
10
Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
11
JST, CREST, Kyoto 606-8501, Japan.
12
Platform for Drug Discovery, Informatics, and Structural Life Science, JST, Kyoto 606-8501, Japan.
13
Department of Biochemistry, Keio University School of Medicine, JST, Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo 160-8582, Japan.

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.

PMID:
26988023
PMCID:
PMC4802085
DOI:
10.1038/ncomms11030
[Indexed for MEDLINE]
Free PMC Article

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