Function-related asymmetry of the specific cardiolipin binding sites on the mitochondrial ADP/ATP carrier.

Xiaoting Mao, Shihao Yao, Qiuzi Yi, Zhe-Ming Xu, Xiaohui Cang

Biochimica et biophysica acta. Biomembranes 2021 Jan 01

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The ADP/ATP carrier (AAC) transports matrix ATP and cytosolic ADP across the inner mitochondrial membrane (IMM). It is well known that cardiolipin (CL) plays an important role in regulating the function of AAC, yet the underlying mechanism still remains elusive. AAC is composed of three homologous domains, and three specific CL binding sites are located at the domain-domain interfaces near the matrix side. Here we report an in-depth investigation on the dynamic properties of the bound CL within the three specific sites through all-atom molecular dynamics simulations of up to 13 μs in total. Our results highlight the importance of the basic and polar residues in CL binding. The basic residues from the linker helix and/or the [Y/W/F][K/R]G motif enable the bound CL to form an intra-domain binding mode, and the canonical inter-domain binding mode only forms when these basic residues are occupied by an additional phospholipid. Of special significance, differences in the basic and polar residues lead to remarkable asymmetry among the three specific CL binding sites. We found that the bound CL at the interface of domains 2 and 3 predominantly adopts inter-domain binding mode, while CLs at the other two sites have much more intra-domain populations. This is consistent with the asymmetric crystal structure of the matrix state (m-state) AAC which implies an asymmetric transport mechanism. The dynamic equilibrium between the inter-domain and intra-domain binding modes observed in our simulations could be highly important for the bound CLs to adapt to the movements during state transitions. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Xiaoting Mao, Shihao Yao, Qiuzi Yi, Zhe-Ming Xu, Xiaohui Cang. Function-related asymmetry of the specific cardiolipin binding sites on the mitochondrial ADP/ATP carrier. Biochimica et biophysica acta. Biomembranes. 2021 Jan 01;1863(1):183466