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. 2022 Mar 26;298(5):101870. doi: 10.1016/j.jbc.2022.101870

Figure 4.

Figure 4

Targeting signal sequences for preprotein import by the TOM complex. Proteins imported across the OMM, with various mitochondrial subcompartments as their destination, possess cleavable or noncleavable sequences and can be charged or hydrophobic. The import is orchestrated by a specific TOM complex receptor, and the molecular pathway used by the preprotein within the Tom40 channel is dictated by the polarity of the targeting sequence. Preprotein pathways (A; orange) and (B; magenta), destined for the IMM and matrix respectively, carry an N-terminal cleavable signal sequence, recognized by Tom20. Tom22 interacts with TIM23 of the IMM for coordinated preprotein handover between both OMM and IMM import machineries. TIM23 triggers lateral release of the processed polypeptide in the IMM (A) or completes the import into the matrix (B), after processing by mitochondrial processing peptidases (MPP). IMS proteins with a Cys-rich internal hydrophobic signal sequence (pathway C; brown) are imported in a Tom22-depleted dimeric Tom40 (50). The preprotein is handed over to the IMM-anchored MIA machinery, which catalyzes disulfide bond formation and release of these polypeptides in the IMS. (D; green) OMM β-barrels with a noncleavable C-terminal internal β-signal sequence are recognized first by Tom70 followed by Tom22, for import through Tom40. Tim9–Tim10 holdases handover the unfolded polypeptide to the SAM complex for assembly in the OMM. Carrier proteins (E; blue) are imported first through Tom70–Tom40, carried by small Tims to TIM22, for their import and release in the IMM. (F; purple) Transmembrane helices of the OMM with a noncleavable signal anchor sequence are imported by MIM directly into the OMM, with assistance only from Tom70. Figure inspired from (2, 9, 187). IMM, inner mitochondrial membrane; IMS, intermembrane space; MIA, mitochondrial intermembrane space assembly; MIM, mitochondrial import machinery; OMM, outer mitochondrial membrane; SAM, sorting and assembly machinery; TIM, translocase of the inner mitochondrial membrane; TOM, translocase of the outer mitochondrial membrane.