Roles of molecular chaperones in protein import into mitochondria.

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Most nuclear encoded mitochondrial precursor proteins are synthesized with amino-terminal presequences that are characterized by positive charge and amphiphilicity. The post-translational targeting of mitochondrial precursors to mitochondria is often facilitated by cytosolic chaperones including members of hsp70 stress protein family. We have studied the interactions of various synthetic peptides with unfolded proteins and yeast cytosolic hsp70, Ssalp. We found that mitochandrial presequences could induce aggregation of the unfolded proteins, suggesting that mitochondrial presequences can interact with the mature part of a precursor during the folding process and cause aggregation. We next found that mitochondrial presequences could bind to Ssalp and that the interactions of presequences with Ssalp are directly correlated with the amphiphilicity of the presequences. Taken together, the present results suggest that hsp70 can prevent aggregation by binding to the presequence as well as the unfolded mature part. While associated with hsp70, the presequence should be prevented from interacting with the newly synthesized, unfolded part of the precursor and would not be able to induce aggregation of these proteins in the cytosol.It is known that in E.coli, the function of DnaK (bacterial hsp70) is regulated by two other heat shock proteins, DnaJ and GrpE.We have revealed here that Ygelp, a yeast GrpE homolog, is a soluble protein in the mitochondrial matrix. Depletion of Ygelp in yeast cells resulted in accumulation of the mitochondrial precursor proteins, suggesting that Ygelp is involved in protein import into mitochondria. These results and others suggest that Ygelp functions in cooperation with Ssclp, a mitochondrial hsp70, and facilitates protein import into mitochondria.