Year: 2026
Type: preprint
Abstract: Most mitochondrial proteins are produced in the cytosol and imported through the translocase of the outer mitochondrial membrane (TOM) to reach their final destination. Although this protein entry gate has been structurally characterized, it remains unclear how precursor proteins are handed off from the cytosolic receptor domains to the translocation pore. Here we show that the cytosolic domain of Tom22-traditionally viewed as the central TOM receptor-acts not as a structured scaffold but as a largely disordered, flexible segment that plays an active role in precursor transfer. Atomic-level structural techniques and in vivo experiments identified a conserved short linear motif that forms a transient α-helical element within this disordered domain. By binding to the canonical precursor protein binding sites of the receptors Tom20 and Tom70, this critical α-helical segment acts as a precursor protein displacement element (PPDE). This competitive interaction facilitates the release of preproteins directly above the import pore, and thereby drives translocation across the outer mitochondrial membrane. These findings reveal that flexibility, rather than rigid structure, underlies the central transfer step of mitochondrial outer-membrane protein translocation. Our results point to a versatile mechanism for ligand displacement in chaperone, receptor, and transport systems that must balance selective binding with efficient release.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Institute of Science and Technology Austria, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Austrian Science Fund, Centre National de la Recherche Scientifique, French Infrastructure for Integrated Structural Biology, National Institutes of Health, National Institute of General Medical Sciences
Awards: G1014860659, CBH-EUR-GS, G1514386576, G2127359846, G2247417377, G256544642, G259924242, G2659019386, G2921176495, Structural and functional studies of import and intermembrane space transfer of mitochondrial membrane proteins, G3232485578, G4656594441, G476804481, EXC 2189: CIBSS Centre for Integrative Biological Signalling Studies, G502948375, G5499690747, Strukturelle und funktionelle Untersuchungen des Imports und Intermembranraumtransfers von mitochondrialen Membranproteinen, G6803667113, G7237471465, G7240651115, SFB 1381: Dynamische Organisation zellulärer Proteinmaschinerien: Von der Biogenese und modularen Assemblierung zur Funktion, G9000053038
OpenAlex ID: W7124136469