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KAKEN_15K07011seika.pdf
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:Nov 12, 2018 |
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| Title |
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膜結合性ヘムタンパク質PGRMC1の構造的制御による生理機能の解明
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マク ケツゴウセイ ヘムタンパクシツ PGRMC1 ノ コウゾウテキ セイギョ ニ ヨル セイリ キノウ ノ カイメイ
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Maku ketsugōsei hemutanpakushitsu PGRMC1 no kōzōteki seigyo ni yoru seiri kinō no kaimei
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Analysis of functional regulation of PGMRC1
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加部, 泰明
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カベ, ヤスアキ
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Kabe, Yasuaki
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慶應義塾大学・医学部(信濃町)・専任講師
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科研費研究者番号 : 20397037
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内田, 毅
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ウチダ, タケシ
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Uchida, Takeshi
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北海道大学・理学部・准教授
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Research team member
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科研費研究者番号 : 30343742
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2018
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科学研究費補助金研究成果報告書
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2017
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本研究では, 新規のガス応答性因子として同定した膜タンパク質タンパク質PGRMC1の構造的機能制御の解明を行った。X線結晶構造解析により, PGRMC1はチロシン残基のヘム配位によって, 突出したヘム同士が重なり合った特異な重合体構造を形成することを見出し, 生体内ガスCOがこの重合が解離してPGRMC1の機能を阻害することを見出した。PGRMC1はがん細胞内のヘム濃度に応答して重合化することにより活性化し, がん増殖に関わるEGFRと会合してがん増殖シグナルを増強するという, ダイナミックな構造変換によって機能することを明らかとした(Nature Commun 2017)。
Progesterone receptor membrane component 1 (PGRMC1) 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. Crystallographic analyses revealed that PGRMC1 forms a stable dimer through stacking interactions of two protruding haem molecules. The haem iron is five-coordinated by Tyr113. Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs. 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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研究種目 : 基盤研究(C)(一般)
研究期間 : 2015～2017
課題番号 : 15K07011
研究分野 : 生物学
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