We have studied the interactions between various synthetic peptides and two model unfolded proteins, reduced α-lactalbumin and reduced and carboxymethylated α-lactalbumin. We found that mitochondrial presequences could induce aggregation of the unfolded α-lactalbumins but not of the native α-lactalbumin. The presequence-induced aggregation of unfolded α-lactalbumin was dependent on electrostatic interactions and on the amphiphilicity of the presequences. Since positive charge and amphiphilicity are necessary for the targeting function of mitochondrial presequences, presequence-induced aggregation may be responsible for the instability of mitochondrial precursor proteins and may need to be inhibited by binding factors in the cytosol.
