Accessory signals in protein translocation

A large fraction of the polypeptides synthesized in the cytosol of eukaryotic cells carry targeting signals to direct them to specific cellular compartments [1]. Proteins that reach their target compartment in an unfolded conformation typically display their targeting signals at their N-termini. Examples are the signal sequences of secretory proteins, the matrix targeting sequences (MTSs, also called presequences) of mitochondrial proteins, the transit peptides of chloroplast proteins as well as bacterial leader peptides. These Nterminal targeting signals are necessary and sufficient for protein translocation. If fused to almost any protein, they reliably drag their fusion partner into their respective compartment. In most cases, they are removed from the mature segments of the proteins by processing peptidases subsequent to the translocation reaction. A number of recent studies, however, showed that the information relevant for protein targeting to the mitochondrial matrix is not only restricted to the Nterminal targeting sequences, but additional accessory signals in the mature regions of precursor proteins can considerably influence protein translocation [2, 3]. While these signals are dispensable for targeting per se, they appear to be decisive for the efficiency and velocity of the translocation reaction. These internal sequences presumably fulfill different functions, in particular in the association with cytosolic chaperones and with receptor proteins exposed on membrane surfaces. These accessory signals thereby counteract the folding or even drive the untangling of (loosely) folded cytosolic precursors (Fig. 1). The MTSs of mitochondrial proteins form amphiphatic helices with one hydrophobic and one positively charged surface. Recently, it was observed that segments of similar characteristics are scattered along the mature sequences of many mitochondrial proteins [2]. Given their similarity to presequences, they were named internal matrix targeting signal-like sequences (iMTS-Ls). Prediction programs such as TargetP, normally designed to identify MTSs, can easily be utilized to recognize iMTS-Ls [2]. The iMTS-Ls bind to the mitochondrial surface receptor Tom70. Tom70 belongs to the tricopeptide repeat (TPR) protein family, members of which serve as cofactors of Hsp70 and Hsp90 chaperones. Thus, mitochondrial precursor proteins obviously contain defined binding sites for a mitoEditorial