Abstract
Mitochondrial ATP-Mg/Pi carriers import adenine nucleotides into the mitochondrial matrix and export phosphate to the cytosol. They are calcium-regulated to control the size of the matrix adenine nucleotide pool in response to cellular energetic demands. They consist of three domains: an N-terminal regulatory domain containing four calcium-binding EF-hands, a linker loop domain with an amphipathic α-helix and a C-terminal mitochondrial carrier domain for the transport of substrates. Here, we use thermostability assays to demonstrate that the carrier is regulated by calcium via a locking pin mechanism involving the amphipathic α-helix. When calcium levels in the intermembrane space are high, the N-terminus of the amphipathic α-helix is bound to a cleft in the regulatory domain, leading to substrate transport by the carrier domain. When calcium levels drop, the cleft closes, and the amphipathic α-helix is released to bind to the carrier domain via its C-terminus, locking the carrier in an inhibited state.
Highlights
The ATP-Mg/Pi carrier (APC) is a member of the mitochondrial carrier family of transport proteins[1,2,3]
There was no significant difference in the specific initial rate of ATP uptake catalysed by ATP-Mg/Pi carrier isoform 1 (APC1) in the presence or absence of internal calcium
These results show that calcium-dependent activation could be observed for the isolated and reconstituted human APC1, demonstrating that it is fully active
Summary
The ATP-Mg/Pi carrier (APC) is a member of the mitochondrial carrier family of transport proteins[1,2,3]. The impact of APC2 (SCaMC3/SLC25A23) knockouts has been studied in mouse liver[6], mouse neuronal tissue[7,8], and that of an APC3 (SCaMC2/SLC25A25) knockout in a mouse model[9] These studies highlighted the requirement for adenine nucleotide movement in and out of mitochondria for respiratory function and protection against calcium-induced permeabilisation of the mitochondrial inner membrane in stress conditions[10]. The C-terminal carrier domain is involved in substrate transport across the mitochondrial inner membrane[14] and has the structural fold of mitochondrial carriers It consists of three homologous sequence repeats[15], each containing two membrane-spanning α-helices connected by a matrix α-helix[16]. The effects of calcium on isolated human APC1 reconstituted into liposomes has not been reported[2]
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