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

被引：155

作者：

Kabe, Yasuaki ^{[1
,2
]}

Nakane, Takanori ^{[3
,4
]}

Koike, Ikko ^{[1
,2
]}

Yamamoto, Tatsuya ^{[5
]}

Sugiura, Yuki ^{[1
,2
]}

Harada, Erisa ^{[5
]}

Sugase, Kenji ^{[5
]}

Shimamura, Tatsuro ^{[3
]}

Ohmura, Mitsuyo ^{[1
,2
]}

Muraoka, Kazumi ^{[1
,2
]}

Yamamoto, Ayumi ^{[6
]}

Uchida, Takeshi ^{[6
]}

Iwata, So ^{[3
,7
]}

Yamaguchi, Yuki ^{[8
]}

Krayukhina, Elena ^{[9
]}

Noda, Masanori ^{[9
]}

Handa, Hiroshi ^{[10
]}

Ishimori, Koichiro ^{[6
]}

Uchiyama, Susumu ^{[9
,11
]}

Kobayashi, Takuya ^{[3
,12
,13
]}

Suematsu, Makoto ^{[14
]}

机构：

[1] Keio Univ, Sch Med, Dept Biochem, Tokyo 1608582, Japan

[2] Japan Sci & Technol Agcy JST, CREST, Tokyo 1608582, Japan

[3] Kyoto Univ, Grad Sch Med, Dept Med Chem & Cell Biol, Kyoto 6068501, Japan

[4] Kyoto Univ, Grad Sch Med, Dept Stat Genet, Kyoto 6068501, Japan

[5] Suntory Fdn Life Sci, Bioorgan Res Inst, Kyoto 6190284, Japan

[6] Hokkaido Univ, Fac Sci, Dept Chem, Sapporo, Hokkaido 0600810, Japan

[7] JST, Res Accelerat Program, Membrane Prot Crystallog Project, Kyoto 6068501, Japan

[8] Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Biol Informat, Yokohama, Kanagawa 2268501, Japan

[9] Osaka Univ, Grad Sch Engn, Dept Biotechnol, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan

[10] Tokyo Med Univ, Dept Nanoparticle Translat Res, Tokyo 1608402, Japan

[11] Natl Inst Nat Sci, Okazaki Inst Integrat Biosci, 5-1 Higashiyama, Okazaki, Aichi 4448787, Japan

[12] JST, CREST, Kyoto 6068501, Japan

[13] JST, Platform Drug Discovery Informat & Struct Life Sc, Kyoto 6068501, Japan

[14] Keio Univ, Sch Med, Dept Biochem, JST,Exploratory Res Adv Technol ERATO,Suematsu Ga, Tokyo 1608582, Japan

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

日本科学技术振兴机构;

关键词：

PROGESTERONE-RECEPTOR; CARBON-MONOXIDE; SIGMA-2; RECEPTOR; STRUCTURAL BASIS; MEMBRANE COMPONENT-1; PROTEIN; PGRMC1; IRON; OXYGENASE; BINDING;

D O I：

10.1038/ncomms11030

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 angstrom 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.

引用

页数：13

共 66 条

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