12PB

Single particle cryo-EM structure of human MTCH2 (hyperactive mutant K25E Y235A V238D)

Summary for 12PB

• Entry DOI: 10.2210/pdb12pb/pdb
• EMDB information: 76659
• Descriptor: UCP1 Nanobody, Mitochondrial carrier homolog 2,Mitochondrial brown fat uncoupling protein 1 (2 entities in total)
• Functional Keywords: mitochondrial outer membrane insertase, slc25 carrier fold, hydrophilic groove, membrane protein biogenesis, membrane protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 2
• Total formula weight: 47394.53

Authors

Luo, Z.,Stevens, T.A.,Voorhees, R.M. (deposition date: 2026-04-14, release date: 2026-05-13, Last modification date: 2026-07-08)

Primary citation

Stevens, T.A.,Luo, Z.,Lee, C.,Hazu, M.,Galatis, E.G.,Inglis, A.J.,Guna, A.,Voorhees, R.M.
Structural evolution of the MTCH family of mitochondrial insertases.
Sci Adv, 12:eaeh2957-eaeh2957, 2026

PubMed Abstract: 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.

PubMed: 42308315
DOI: 10.1126/sciadv.aeh2957

Experimental method

ELECTRON MICROSCOPY (3.1 Å)