电压依赖性阴离子选择性通道1VDAC1)是一种β桶蛋白,在人类中是由5号染色体上的VDAC1基因所製造[4][5]。此蛋白質會在线粒体外膜(OMM)和细胞膜中形成离子通道:在OMM上,ATP通過該離子通道而能自线粒体扩散至细胞质;在细胞膜中,VDAC1則参与体积的调节。在所有真核细胞中,线粒体皆負責ATP的合成,並同時合成其他细胞存活所需的代谢物,VDAC1也因而參與线粒体和细胞间的通信,進而調節细胞代谢和死亡之间的平衡。除代谢物的渗透外,VDAC1还可作为己糖激酶等蛋白质的支架,參與代謝過程的調節。[6]

VDAC1
已知的結構
PDB直系同源搜索: PDBe RCSB
識別號
别名VDAC1;, PORIN, VDAC-1, voltage dependent anion channel 1
外部IDOMIM604492 MGI106919 HomoloGene107244 GeneCardsVDAC1
RNA表达模式


查阅更多表达数据
直系同源
物種人類小鼠
Entrez
Ensembl
UniProt
mRNA​序列

​NM_003374

NM_011694
​NM_001362693

蛋白序列

NP_003365

基因位置​(UCSC)无数据Chr 11: 52.36 – 52.39 Mb
PubMed​查找[2][3]
維基數據
檢視/編輯人類檢視/編輯小鼠

该蛋白质是电压依赖性阴离子通道,与其他VDAC同种型(VDAC2VDAC3)具有高度结构同源性,其参与细胞代谢线粒体凋亡和精子发生的调节。[7][8][9][10]该通道的过度表达和错误调节可导致细胞凋亡,导致体内多种疾病。特别是,由于VDAC1是主要的阴离子离子转运通道,其功能障碍与癌症,帕金森病(PD)和阿尔茨海默病有关。[11][12][13]

结构

编辑

三种VDAC同种型(VDAC1,VDAC2和VDAC3)具有高度保守的DNA序列以及形成宽β-桶结构的3D结构,其中α螺旋N-末端区段驻留以部分闭合通道。[14]VDAC1的结构由3个独立的实验室通过X射线晶体学,核磁共振(NMR)光谱学或两者的组合来解决。这些结构研究中的两个用于确定人VDAC1(hVDAC1)结构,而X射线晶体学用于解决鼠VDAC1(mVDAC1)结构,其仅与hVDAC1相差仅两个残基。[15][16][17]这些确定的结构与先前的圆二色研究一致,该研究预测了α螺旋和β链结构域的存在。[18]

mVDAC1的结构分析显示由19个两亲性β-链组成的桶状通道,其N-末端和C-末端均朝向线粒体的膜间隙。[19][20]β-链通过环转连接并以反平行模式排列,除了平行的β-链1和19。[17]通道的高度为40Ẳ,在开口处跨越27Ẳ-20Ẳ的距离,并在打开状态下在N端α-螺旋段处逐渐减小至20Ẳ×14Ẳ。[21]闭合状态构象尚未被确定。另外,N-末端具有α螺旋区段,其通过与β-折叠8-18链上的残基的疏水相互作用而保持在通道的内壁。[17]该N-末端可以用作离子移动或蛋白质附着的支架。一个这样的例子被看作是HK1结合的位点。[6]要指出的重要残基是位于氨基酸链上第73个残基的谷氨酸(E73)。该残基存在于VDAC1和VDAC2中,但不存在于VDAC3中。该带电残基的侧链指向磷脂双层,这通常会引起排斥力。然而,E73与VDAC1功能和相互作用有关。[22]

功能

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VDAC1属于线粒体孔蛋白家族,并且预测与其他VDAC同种型具有相似的生物学功能。[23]在三种同种型中,VDAC1是主要的钙离子转运通道,并且转录最多。[12][24]VDAC1通过在线粒体外膜(OMM)上运输ATP和其他小代谢物参与细胞代谢,从而允许调节TCA循环,并通过延伸,调节活性氧ROS)的产生。[11]在酵母细胞中,ROS响应于氧化应激而累积,这导致线粒体功能受损和“小”表型。然而,小型酵母细胞表现出比野生型细胞更长的寿命,并且表明VDAC1在例如衰老类似情况下的保护功能。[6][24]

临床意义

编辑

电压依赖性阴离子通道在离子和代谢物转运中都起作用,尽管它们的生理作用是不同的。由于它们的作用,通道的功能障碍可导致各种疾病。 VDAC1通过与抗凋亡蛋白家族Bcl-2蛋白,特别是Bcl-xl和Mcl-1的相互作用而与癌症有关,这些蛋白在癌症过程中过表达。这两种Bcl-2蛋白与VDAC1相互作用以调节穿过OMM的钙离子转运,并最终调节ROS的产生。虽然高水平的ROS诱导细胞死亡,但非致死水平会干扰信号转导通路,从而促进癌细胞的细胞增殖,迁移和侵袭。[11]此外,VDAC1过表达与增加的凋亡反应和抗癌药物和治疗功效相关,进一步支持VDAC1作为癌症治疗的治疗靶标。[11][25]

VDAC1在钙离子转运中的功能也与神经退行性疾病有关。在PD中,VDAC1增加线粒体内的钙离子水平,导致线粒体通透性增加,线粒体膜电位破坏,ROS产生增加,细胞死亡和神经元变性。[12]已显示VDAC1与淀粉样蛋白β(Aβ)相互作用,导致通道的电导增加并最终导致细胞凋亡。[13]

参考文献

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