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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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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802085/
https://www.ncbi.nlm.nih.gov/pubmed/26988023
http://dx.doi.org/10.1038/ncomms11030
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author 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
author_facet 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
author_sort Kabe, Yasuaki
collection PubMed
description 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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spelling pubmed-48020852016-03-25 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 Nat Commun Article 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. Nature Publishing Group 2016-03-18 /pmc/articles/PMC4802085/ /pubmed/26988023 http://dx.doi.org/10.1038/ncomms11030 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
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
Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance
title Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance
title_full Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance
title_fullStr Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance
title_full_unstemmed Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance
title_short Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance
title_sort haem-dependent dimerization of pgrmc1/sigma-2 receptor facilitates cancer proliferation and chemoresistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802085/
https://www.ncbi.nlm.nih.gov/pubmed/26988023
http://dx.doi.org/10.1038/ncomms11030
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