Abstract
Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical SLC25 (solute carrier family 25) mitochondrial carriers, the past decade has led to the discovery of additional protein families with numerous members that exhibit IMM localization and transporter-like properties. These include mitochondrial pyruvate carriers, sideroflexins, and mitochondrial cation/H+ exchangers. These transport proteins were linked to vital physiological functions and disease. Their structures and transport mechanisms are, however, still largely unknown and understudied. Protein sequence analysis per se can often pinpoint hotspots that are of functional or structural importance. In this review, we summarize current knowledge about the sequence features of mitochondrial transporters with a special focus on the newly included SLC54, SLC55 and SLC56 families of the SLC solute carrier superfamily. Taking a step further, we combine sequence conservation analysis with transmembrane segment and secondary structure prediction methods to extract residue positions and sequence motifs that likely play a role in substrate binding, binding site gating or structural stability. We hope that our review will help guide future experimental efforts by the scientific community to unravel the transport mechanisms and structures of these novel mitochondrial carriers.
Highlights
Mitochondria are believed to have evolved through an endosymbiotic event, where an α-proteobacteria has been engulfed by a host cell, possibly an archaeon [1,2]
The spectrum of primary and secondary active transporters in the mitochondrial inner membrane has greatly broadened in the past decade through the functional identification of mitochondrial pyruvate carriers, sideroflexins, and other mitochondrial transporters such as SLC8B1
This plurality of inner mitochondrial membrane (IMM) transporters that show marked dissimilarity to SLC25 carriers, with no apparent common evolutionary history to the SLC25 family, hints that many other, as of yet unidentified secondary transporter families could exist in mitochondria
Summary
Mitochondria are believed to have evolved through an endosymbiotic event, where an α-proteobacteria has been engulfed by a host cell, possibly an archaeon [1,2]. Close helix-helix contacts in the matrix-facing state are formed by two conserved sequence motifs, πGπxπG on the odd-numbered, and πxxxπ on the even-numbered helices, where π stands for a residue with a small side-chain [45,47,48] Further details of these sequence motifs, including their roles in the transport mechanism and a functional interpretation of individual amino acid residues is covered in detail by Kunji et al in this special issue. The sequence motif (QYKGxxDCxRK) in the short matrix helices has been described, which is only conserved in a subset of mitochondrial carriers, such as ADP/ATP (SLC25A4–6, SLC25A31), aspartate/glutamate (SLC25A12–13), ornithine (SLC25A2, SLC25A15), glutamate (SLC25A18, SLC25A22), and carnitine (SLC25A20) carriers, one ATP/Pi carrier (SLC25A24) and three carriers with unknown function (SLC25A9, SLC25A34, SLC25A45) [50] This motif was proposed to harbor residues that go through post-translational modification thereby locally altering the protein structure and modulating function. The detailed investigation of these residues in future studies might reveal more about their role in transporter function
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