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Structural evolution of the MTCH family of mitochondrial insertases

Stevens, T. A.; Luo, Z.; Lee, C.; Hazu, M.; Galatis, E. G.; Inglis, A. J.; Guna, A.; Voorhees, R. M.

2026-02-18 cell biology
10.64898/2026.02.17.705849 bioRxiv
Show abstract

Here we demonstrated that MTCH2 is the defining member of a large family of mitochondrial outer membrane (OM) insertases. The MTCH family is conserved across holozoa and has diverged from the solute carrier 25 transporters. The cryoelectron microscopy structure of the 33 kDa human MTCH2 revealed that evolution of its insertase activity required loss of a transmembrane helix, which created a lipid-accessible hydrophilic groove stabilized by its unique, structured C-terminus. Mutational analyses showed that MTCH insertase activity is attenuated, while experimental structures of hyperactive mutants demonstrated that the hydrophobicity, charge, and size of the residues that line its groove regulated MTCH function. Leveraging the MTCH2 structure, we identified the plant OM insertase, and proposed a universal mechanism for OM insertion across all kingdoms of life.

Published in Science Advances (predicted rank #2) · training set

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