C subunit of the ATP synthase is an amyloidogenic calcium dependent channel-forming peptide with possible implications in mitochondrial permeability transition.
C subunit of the ATP synthase is an amyloidogenic calcium dependent channel-forming peptide with possible implications in mitochondrial permeability transition.
复制标题
DOI：
10.1038/s41598-021-88157-z
复制
发表时间：
2021-04-22
影响因子：
4.6
通讯作者：
Pavlov EV
中科院分区：
文献类型：
--
作者：
Amodeo GF;Lee BY;Krilyuk N;Filice CT;Valyuk D;Otzen DE;Noskov S;Leonenko Z;Pavlov EV
c 亚基是由三个核基因编码的线粒体内膜 (IMM) 蛋白。 c 亚基最为人所知的是 ATP 合酶 F0 复合物的组成部分，它也存在于蜡状脂褐质的其他细胞质区室中。在生理条件下，这种 75 个残基长的肽折叠成 α-螺旋发夹并形成跨越脂质双层的寡聚物。除了其生理作用外，c 亚基还被认为是通过钙诱导的通透性转变机制，作为应激诱导的 IMM 通透化的关键参与者。然而，c亚基参与IMM透化的分子机制尚不完全清楚。在这里，我们使用荧光光谱、原子力显微镜和黑色脂质膜方法来深入了解未修饰的 c 亚基蛋白的结构和功能特性，这些特性可能使其与线粒体毒性相关。我们发现c亚基是一种淀粉样肽，可以自发折叠成β-折叠并以Ca2+依赖性方式自组装成原纤维和寡聚体。 C 亚基寡聚物在脂膜中表现出离子通道活性。我们认为 c 亚基的毒性作用可能与其淀粉样蛋白生成特性有关，并由类似于 Aβ 和 α-突触核蛋白等神经退行性多肽的机制驱动。
The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes. Best known as an integral part of the F0 complex of the ATP synthase, the c subunit is also present in other cytoplasmic compartments in ceroid lipofuscinoses. Under physiological conditions, this 75 residue-long peptide folds into an α-helical hairpin and forms oligomers spanning the lipid bilayer. In addition to its physiological role, the c subunit has been proposed as a key participant in stress-induced IMM permeabilization by the mechanism of calcium-induced permeability transition. However, the molecular mechanism of the c subunit participation in IMM permeabilization is not completely understood. Here we used fluorescence spectroscopy, atomic force microscopy and black lipid membrane methods to gain insights into the structural and functional properties of unmodified c subunit protein that might make it relevant to mitochondrial toxicity. We discovered that c subunit is an amyloidogenic peptide that can spontaneously fold into β-sheets and self-assemble into fibrils and oligomers in a Ca2+-dependent manner. C subunit oligomers exhibited ion channel activity in lipid membranes. We propose that the toxic effects of c subunit might be linked to its amyloidogenic properties and are driven by mechanisms similar to those of neurodegenerative polypeptides such as Aβ and α-synuclein.
登录
查看更多内容
影响因子：
4.3
作者：
Bonora, Massimo;Bononi, Angela;Pinton, Paolo
通讯作者：
Pinton, Paolo
影响因子：
4
作者：
Angelova PR;Ludtmann MH;Horrocks MH;Negoda A;Cremades N;Klenerman D;Dobson CM;Wood NW;Pavlov EV;Gandhi S;Abramov AY
通讯作者：
Abramov AY
DOI：
10.1006/bbrc.2000.3231
发表时间：
2000-08-11
影响因子：
3.1
作者：
McGeoch, JEM;McGeoch, MW;Guidotti, G
通讯作者：
Guidotti, G
DOI：
10.1073/pnas.1401591111
发表时间：
2014-07-22
影响因子：
11.1
作者：
Alavian, Kambiz N.;Beutner, Gisela;Jonas, Elizabeth A.
通讯作者：
Jonas, Elizabeth A.
DOI：
10.1073/pnas.90.2.567
发表时间：
1993-01-15
影响因子：
11.1
作者：
ARISPE, N;ROJAS, E;POLLARD, HB
通讯作者：
POLLARD, HB