The mitochondrial Tim chaperones are responsible for the transport of membrane proteins across the inter-membrane space to the inner and outer mitochondrial membranes. TIM9·10, a hexameric 70 kDa protein complex formed by 3 copies of Tim9 and Tim10, guides its clients across the aqueous compartment. The TIM9·10·12 complex is the anchor point at the inner-membrane insertase complex TIM22. The mechanism of client transport by TIM9·10 has been resolved recently, but the structure and subunit composition of the TIM9·10·12 complex remains largely unresolved. Furthermore, the assembly process of the hexameric TIM chaperones from its subunits remained elusive. We investigate the structural and dynamical properties of the Tim subunits, and show that they are highly dynamic. In their non-assembled form, the subunits behave as intrinsically disordered proteins; when the conserved cysteines of the CX3C-Xn-CX3C motifs are formed, short marginally stable α-helices are formed, which are only fully stabilized upon hexamer formation to the mature chaperone. Subunits are in equilibrium between their hexamer-embedded and a free form, with exchange kinetics on a minutes time scale. Joint NMR, small-angle X-ray scattering and MD simulation data allow us to derive a structural model of the TIM9·10·12 assembly, which has a 2:3:1 stoichiometry with a conserved hydrophobic client- binding groove and flexible N- and C-terminal tentacles.
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