Abstract
The proper distribution of proteins between the cytosol and various membrane-bound compartments is crucial for the functionality of eukaryotic cells. This requires the cooperation between protein transport machineries that translocate diverse proteins from the cytosol into these compartments and targeting signal(s) encoded within the primary sequence of these proteins that define their cellular destination. The mechanisms exerting protein translocation differ remarkably between the compartments, but the predominant targeting signals for mitochondria, chloroplasts and the ER share the N-terminal position, an α-helical structural element and the removal from the core protein by intraorganellar cleavage. Interestingly, similar properties have been described for the peroxisomal targeting signal type 2 mediating the import of a fraction of soluble peroxisomal proteins, whereas other peroxisomal matrix proteins encode the type 1 targeting signal residing at the extreme C-terminus. The structural similarity of N-terminal targeting signals poses a challenge to the specificity of protein transport, but allows the generation of ambiguous targeting signals that mediate dual targeting of proteins into different compartments. Dual targeting might represent an advantage for adaptation processes that involve a redistribution of proteins, because it circumvents the hierarchy of targeting signals. Thus, the co-existence of two equally functional import pathways into peroxisomes might reflect a balance between evolutionary constant and flexible transport routes.
Highlights
The similarity of the PTS2 and other N-terminal targeting signals might represent a functional distinction between the PTS1 and the PTS2, because it is conceivable that PTS2 motifs can be part of an ambiguous targeting signal that concomitantly targets a protein into peroxisomes and another organelle
All transport routes are accessible by N-terminal targeting signals that involve an α-helical domain, which interact with the appropriate receptor protein to initiate translocation
In spite of the structural similarity between these N-terminal targeting signals the distribution of the majority of cellular proteins is welldefined, highlighting the specificity of the transport processes. This specificity is enhanced by unique properties of the targeting signals, which render them suitable for a classification into a type of targeting signal (PTS2, presequence, transit peptide, signal peptide), these targeting signals are not highly conserved, but rather degenerate
Summary
An elaborate endomembrane system separates the cytosolic space from sealed compartments such as mitochondria, peroxisomes, chloroplasts (in plants), and the secretory (endoplasmic reticulum (ER), golgi, trans golgi network (TGN), and lysosome) and endosomal (early and late endosomes) system, which we generally summarize as organelles within this review. The destination of individual proteins is encoded within their primary sequence in the form of short peptides called targeting signals, which can be considered postal codes necessary and sufficient to determine the intracellular location These targeting signals are recognized by receptor proteins, which are the frontline of the organellar import machinery and initiate transport of their cargo proteins (Blobel and Dobberstein, 1975). Similarity to other N-terminal targeting signals distinguishes this PTS (PTS2) from the predominant PTS (PTS1) residing at the C-terminus, which could serve as explanation for the existence of two completely independent PTS that exceeds simple redundancy In this context, we discuss the specificity of targeting signals, the hierarchy of transport routes and the possibility to change the subcellular location of a protein in evolutionary adaptation processes
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