Structural basis of Sorcin-mediated calcium-dependent signal transduction.
Structural basis of Sorcin-mediated calcium-dependent signal transduction.
复制标题
DOI：
10.1038/srep16828
复制
发表时间：
2015-11-18
影响因子：
4.6
通讯作者：
Colotti G
中科院分区：
文献类型：
--
作者：
Ilari A;Fiorillo A;Poser E;Lalioti VS;Sundell GN;Ivarsson Y;Genovese I;Colotti G
索尔菌素是一种必需的五联型手性钙结合蛋白，能够赋予药物敏感的癌细胞多药耐药表型，减少内质网应激和细胞死亡。索尔菌素沉默阻止有丝分裂过程中的细胞周期进程，并通过触发细胞凋亡来诱导细胞死亡。在正常细胞和癌细胞中，Sorcin参与钙稳态的调节和钙依赖的细胞信号转导。索尔辛作用的分子基础尚不清楚。在载脂蛋白(ApoSor)和钙结合形式(CaSor)中Sorcin的X射线结构揭示了Sorcin作用的结构基础：与EF1-3手结合的钙促进了大的构象变化，涉及将EF1-EF2亚区连接到EF3的长D-螺旋移动到EF3并打开EF1。这一运动促进了疏水口袋的暴露，它可以在CaSor中容纳其N-末端结构域的一部分，该部分展示了通过噬菌体展示实验确定的共识结合基序。这个结构域抑制了Sorcin与PDCD6的相互作用，PDCD6是一种携带Sorcin共识基序的蛋白质，与Sorcin共同定位于细胞的核周区和中体，并参与了细胞凋亡的开始。
Sorcin is an essential penta-EF hand calcium binding protein, able to confer the multi-drug resistance phenotype to drug-sensitive cancer cells and to reduce Endoplasmic Reticulum stress and cell death. Sorcin silencing blocks cell cycle progression in mitosis and induces cell death by triggering apoptosis. Sorcin participates in the modulation of calcium homeostasis and in calcium-dependent cell signalling in normal and cancer cells. The molecular basis of Sorcin action is yet unknown. The X-ray structures of Sorcin in the apo (apoSor) and in calcium bound form (CaSor) reveal the structural basis of Sorcin action: calcium binding to the EF1-3 hands promotes a large conformational change, involving a movement of the long D-helix joining the EF1-EF2 sub-domain to EF3 and the opening of EF1. This movement promotes the exposure of a hydrophobic pocket, which can accommodate in CaSor the portion of its N-terminal domain displaying the consensus binding motif identified by phage display experiments. This domain inhibits the interaction of sorcin with PDCD6, a protein that carries the Sorcin consensus motif, co-localizes with Sorcin in the perinuclear region of the cell and in the midbody and is involved in the onset of apoptosis.