The effects of cardiolipin on the structural dynamics of the mitochondrial ADP/ATP carrier in its cytosol-open state

被引:13
作者
Yi, Qiuzi [1 ,2 ,3 ]
Yao, Shihao [1 ,2 ,3 ]
Ma, Boyuan [1 ,2 ,3 ]
Cang, Xiaohui [1 ,2 ,3 ]
机构
[1] Children s Hosp, Div Med Genet & Genom, Hangzhou, Zhejiang, Peoples R China
[2] Zhejiang Univ, Sch Med, Inst Genet, Hangzhou, Zhejiang, Peoples R China
[3] Zhejiang Univ, Sch Med, Dept Genet, Hangzhou, Zhejiang, Peoples R China
基金
中国国家自然科学基金;
关键词
ADENINE-NUCLEOTIDE TRANSLOCASE; GUI MEMBRANE-BUILDER; ADP ATP CARRIER; MOLECULAR-DYNAMICS; CYSTEINE RESIDUES; PROTEIN; TRANSPORT; BINDING; SEQUENCE; BIOSYNTHESIS;
D O I
10.1016/j.jlr.2022.100227
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cardiolipin (CL) has been shown to play a crucial role in regulating the function of proteins in the inner mitochondrial membrane. As the most abundant protein of the inner mitochondrial membrane, the ADP/ATP carrier (AAC) has long been the model of choice to study CL-protein interactions, and specifically bound CLs have been identified in a variety of crystal structures of AAC. However, how CL binding affects the structural dynamics of AAC in atomic detail remains largely elusive. Here we compared all-atom molecular dynamics simulations on bovine AAC1 in lipid bilayers with and without CLs. Our results show that on the current microsecond simulation time scale: 1) CL binding does not significantly affect overall stability of the carrier or structural symmetry at the matrix-gate level; 2) pocket volumes of the carrier and interactions involved in the matrix-gate network become more heterogeneous in parallel simulations with membranes containing CLs; 3) CL binding consistently strengthens backbone hydrogen bonds within helix H-2 near the matrix side; and 4) CLs play a consistent stabilizing role on the domain 1-2 interface through binding with the R30:R71:R151 stacking structure and fixing the M2 loop in a defined conformation. CL is necessary for the formation of this stacking structure, and this structure in turn forms a very stable CL binding site. Such a delicate equilibrium suggests the strictly conserved R30:R71:R151stacking structure of AACs could function as a switch under regulation of CLs. Taken together, these results shed new light on the CL-mediated modulation of AAC function.
引用
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页数:15
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