Abstract
The carrier proteins of the mitochondrial inner membrane consist of three structurally related tandem repeats (modules). Several different, and in some cases contradictory, views exist on the role individual modules play in carrier transport across the mitochondrial membranes and how they promote protein insertion into the inner membrane. Thus, by use of specific translocation intermediates, we performed a detailed analysis of carrier biogenesis and assessed the physical association of carrier modules with the inner membrane translocation machinery. Here we have reported that each module of the dicarboxylate carrier contains sufficient targeting information for its transport across the outer mitochondrial membrane. The carboxyl-terminal module possesses major targeting information to facilitate the direct binding of the carrier protein to the inner membrane twin-pore translocase and subsequent insertion into the inner membrane in a membrane potential-dependent manner. We concluded that, in this case, a single structural repeat can drive inner membrane insertion, whereas all three related units contribute targeting information for outer membrane translocation.
Highlights
All nuclear-encoded mitochondrial proteins contain intrinsic targeting signals that direct them from their site of synthesis in the cytosol to their intended functional location
Outer Membrane—To investigate the location of targeting signals in carrier proteins that direct their translocation into the mitochondrial inner membrane, we made mutants of dicarboxylate carrier 1 (DIC) containing one or two structural repeats, referred to as modules (Fig. 1A)
For both full-length and mutant DIC significant amounts were recovered with protease-treated mitochondria both in the presence or absence of a ⌬ (Fig. 1B, lanes 4 and 5), suggesting that they were efficiently imported across the outer mitochondrial membrane
Summary
Least for receptor recruitment and outer membrane translocation, there is cooperation between each of these domains [31]. The carboxyl-terminal two-thirds of AAC has been implicated in facilitating the later stages of import into mitochondria [38, 39], a more detailed study reports that the import signals that promote inner membrane insertion were contained within the third module [29]. In contrast to these data, a recent report suggests that the third module alone is insufficient to promote membrane insertion but rather that all three modules of the carrier precursor are required to allow membrane insertion via the TIM22 complex [32]. We showed that the third module of DIC contains the dominant targeting signals that allow binding to the twin-pore translocase and promotion of import from Stage III to V
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