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TitleStructural evolution of the MTCH family of mitochondrial insertases.
Journal, issue, pagesSci Adv, Vol. 12, Page eaeh2957, Year 2026
Publish dateApr 14, 2026
AuthorsTaylor A Stevens / Zhilin Luo / Camryn Lee / Masami Hazu / Erini G Galatis / Alison J Inglis / Alina Guna / Rebecca M Voorhees /
PubMed AbstractWe demonstrate that MTCH2 is the defining member of a large family of mitochondrial outer membrane (OM) insertases. MTCH insertases are conserved across holozoa and have diverged from the solute ...We demonstrate that MTCH2 is the defining member of a large family of mitochondrial outer membrane (OM) insertases. MTCH insertases are conserved across holozoa and have diverged from the solute carrier 25 transporters. The cryoelectron microscopy structure of the 33-kilodalton 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 and reconstitution 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.
External linksSci Adv / PubMed:42308315 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.6 Å
Structure data

EMDB-76655, PDB-12oy:
Single particle cryo-EM structure of human MTCH2
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-76656, PDB-12oz:
Single particle cryo-EM structure of human MTCH2 (hyperactive mutant F285N F286N)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-76658: Single particle cryo-EM structure of human MTCH2-BRIL fusion
Method: EM (single particle) / Resolution: 3.55 Å

EMDB-76659, PDB-12pb:
Single particle cryo-EM structure of human MTCH2 (hyperactive mutant K25E Y235A V238D)
Method: EM (single particle) / Resolution: 3.1 Å

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / mitochondrial outer membrane insertase / SLC25 carrier fold / hydrophilic groove / membrane protein biogenesis

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