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

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 analyse...

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Vydáno v:	Nature communications Ročník 7; číslo 1; s. 11030 - 13
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 18.03.2016 Nature Publishing Group Nature Portfolio
Témata:	631/45/612/1237 631/67/1059/2326 631/80/86 96/95 Carbon monoxide Carbon Monoxide - metabolism Cell Proliferation Crystallography, X-Ray Cytochrome P-450 Enzyme System - metabolism Drug Resistance, Neoplasm Heme - metabolism Humanities and Social Sciences Humans Membrane Proteins - metabolism Models, Biological multidisciplinary Neoplasms - metabolism Neoplasms - pathology Protein Binding Protein Multimerization Receptor, Epidermal Growth Factor - metabolism Receptors, Progesterone - metabolism Receptors, sigma - metabolism Science Science (multidisciplinary) Signal Transduction - drug effects Solutions
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. PGRMC1 binds to EGFR and cytochromes P450, and is known to be involved in cancer proliferation and in drug resistance. Here, the authors determine the structure of the cytosolic domain of PGRMC1, which forms a dimer via haem–haem stacking, and propose how this interaction could be involved in its function.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms11030