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bioRxiv · 10.64898/2026.02.13.705746

Rescue of pATOM36-depleted T. brucei by human MTCH1/2 reveals common features of protein insertases

Berger, S.·von Ballmoos, C.·Schneider, A.
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Abstract

Alpha-helically anchored proteins of the mitochondrial outer membrane depend on dedicated insertases, including the MIM complex in yeast, pATOM36 in trypanosomes, and MTCH1/MTCH2 in humans. These insertases lack sequence homology and arose by convergent evolution. Here we show that MTCH1 and an N-terminally modified MTCH2 can replace the OMM biogenesis function of trypanosomal pATOM36, demonstrating functional compatibility across a large phylogenetic distance. Moreover, like other insertases, pATOM36 has lipid scramblase activity and likely induces local membrane thinning. Structural modeling reveals that even though they have inverted membrane topologies, pATOM36 and MTCH1/MTCH2 adopt a similar architecture. They form a hydrophilic cavity comprising five transmembrane helices that is open to both the cytosol and laterally to the membrane core. The same features also extend to the large phylogenetically unrelated YidC-like insertase family of bacterial origin. Together, these findings suggest that membrane protein insertion is constrained to a small number of viable mechanistic solutions, providing evidence for "deterministic" evolution acting at the molecular level.

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Berger, S., von Ballmoos, C., Schneider, A.. 2026-02-16. Rescue of pATOM36-depleted T. brucei by human MTCH1/2 reveals common features of protein insertases. https://doi.org/10.64898/2026.02.13.705746

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