Cryo-EM Structure of the Human Mitochondrial Translocase TIM22 Complex
Mitochondria play vital functions in cellular metabolism, homeostasis, and apoptosis1-3. Most of the mitochondrial proteins are synthesized as precursors in the cytosol and imported into mitochondria for folding or maturation4,5. The translocase TIM22 complex is responsible for the import of multiple hydrophobic carrier proteins that are then folded in the inner membrane of mitochondria6-8. In mammalian cells, the TIM22 complex consists of at least six components, Tim22, Tim29, AGK, and three Tim chaperones (Tim9, Tim10a and Tim10b)9-14. Here, we report the cryo-EM structure of the human translocase TIM22 complex at an overall resolution of 3.7 angstrom. The core subunit, Tim22, contains four transmembrane helices, forming a partial pore that is open to the lipid bilayer. Tim29 is a single transmembrane protein that provides an N-terminal helix to stabilize Tim22 and a C-terminal intermembrane space (IMS) domain to connect AGK and two TIM chaperone hexamers to maintain complex integrity. One TIM hexamer comprises Tim9 and Tim10a in a 3:3 molar ratio, and the other consists of two Tim9 units, three Tim10a units, and one Tim10b unit. The latter hexamer faces the intramembrane region of Tim22, likely providing the dock to load the precursors to the partial pore of Tim22. Our structure serves as a molecular basis for the mechanistic understanding of TIM22 complex function.
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