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Structural Basis of Membrane Protein Chaperoning through the Mitochondrial Intermembrane Space
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International audience. The exchange of metabolites between the mitochon- drial matrix and the cytosol depends on b-barrel channels in the outer membrane and a-helical carrier proteins in the inner membrane. The essential trans- locase of the inner membrane (TIM) chaperones escort these proteins through the intermembrane space, but the structural and mechanistic details remain elusive. We have used an integrated struc- tural biology approach to reveal the functional princi- ple of TIM chaperones. Multiple clamp-like binding sites hold the mitochondrial membrane proteins in a translocation-competent elongated form, thus mimicking characteristics of co-translational mem- brane insertion. The bound preprotein undergoes conformational dynamics within the chaperone bind- ing clefts, pointing to a multitude of dynamic local binding events. Mutations in these binding sites cause cell death or growth defects associated with impairment of carrier and b-barrel protein biogen- esis. Our work reveals how a single mitochondrial ‘‘transfer-chaperone’’ system is able to guide a-heli- cal and b-barrel membrane proteins in a ‘‘nascent chain-like’’ conformation through a ribosome-free compartment.
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