Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782422664037531648 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4802085 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT kabeyasuaki haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT nakanetakanori haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT koikeikko haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT yamamototatsuya haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT sugiurayuki haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT haradaerisa haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT sugasekenji haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT shimamuratatsuro haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT ohmuramitsuyo haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT muraokakazumi haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT yamamotoayumi haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT uchidatakeshi haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT iwataso haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT yamaguchiyuki haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT krayukhinaelena haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT nodamasanori haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT handahiroshi haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT ishimorikoichiro haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT uchiyamasusumu haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT kobayashitakuya haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance AT suematsumakoto haemdependentdimerizationofpgrmc1sigma2receptorfacilitatescancerproliferationandchemoresistance |