Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance.
Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance.
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DOI：
10.1038/ncomms11030
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发表时间：
2016-03-18
影响因子：
16.6
通讯作者：
Suematsu M
中科院分区：
文献类型：
--
作者：
Kabe Y;Nakane T;Koike I;Yamamoto T;Sugiura Y;Harada E;Sugase K;Shimamura T;Ohmura M;Muraoka K;Yamamoto A;Uchida T;Iwata S;Yamaguchi Y;Krayukhina E;Noda M;Handa H;Ishimori K;Uchiyama S;Kobayashi T;Suematsu M
孕激素受体膜组分1（PGRMC 1/Sigma-2受体）是一种含血红素的蛋白质，与表皮生长因子受体（EGFR）和细胞色素P450相互作用，以调节癌症增殖和化疗耐药性;其结构基础尚不清楚。在此，在1.95 nm分辨率下对PGRMC 1胞质结构域的晶体学分析显示，它通过两个突出血红素分子的堆叠相互作用形成稳定的二聚体。血红素铁由Tyr 113五配位，血红素的开放表面介导二聚化。一氧化碳（CO）通过结合到血红素的第六个配位位点来干扰PGRMC 1二聚化。血红素介导的PGRMC 1二聚化是与EGFR和细胞色素P450相互作用、癌症增殖和对抗癌药物的化学抗性所必需的;这些事件通过癌细胞中的CO或血红素剥夺而减弱。这项研究证明了蛋白质通过血红素-血红素堆积的二聚化，这在真核生物中还没有发现，并提供了对其在癌症中的功能意义的见解。 PGRMC 1与EGFR和细胞色素P450结合，并且已知参与癌症增殖和耐药性。在这里，作者确定了PGRMC 1的胞质结构域的结构，该结构域通过血红素-血红素堆积形成二聚体，并提出了这种相互作用如何参与其功能。
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.