Abstract
The import of a subset of peroxisomal matrix proteins is mediated by the peroxisomal targeting signal 2 (PTS2). The results of our sequence and physical property analysis of known PTS2 signals and of a mutational study of the least characterized amino acids of a canonical PTS2 motif indicate that PTS2 forms an amphipathic helix accumulating all conserved residues on one side. Three-dimensional structural modeling of the PTS2 receptor PEX7 reveals a groove with an evolutionarily conserved charge distribution complementary to PTS2 signals. Mammalian two-hybrid assays and cross-complementation of a mutation in PTS2 by a compensatory mutation in PEX7 confirm the interaction site. An unstructured linker region separates the PTS2 signal from the core protein. This additional information on PTS2 signals was used to generate a PTS2 prediction algorithm that enabled us to identify novel PTS2 signals within human proteins and to describe KChIP4 as a novel peroxisomal protein.
Highlights
Type 2 peroxisomal targeting signals (PTS2) tag proteins for import into peroxisomes
Cell biological, and computational methods, we have revealed structural requirements for functional peroxisomal targeting signal 2 (PTS2) signals that are important for their interaction with PEX7
Charged residues at position X3 or a negatively charged residue at position X2 destroy the PTS2 signal, revealing new restrictions for functional PTS2 signals. These restrictions are still too loose to explain the low number of functional PTS2 signals and the strong conservation of PTS2 signals across evolution
Summary
Type 2 peroxisomal targeting signals (PTS2) tag proteins for import into peroxisomes. PTS1 is recognized by its receptor, the peroxin 5 (PEX5) [6, 7], and PTS2 is bound by PEX7 [8, 9] These soluble receptors mediate the transport of their cargo proteins to the peroxisomal surface. Recent investigations primarily analyzed the amino acid frequencies at each position of known PTS2 motifs and of putative PTS2 signals encoded in orthologues of PTS2-carrying proteins [13, 17] without evaluation of physical property patterns of side chains or sequence segment-based properties. Cell biological, and computational methods, we have revealed structural requirements for functional PTS2 signals that are important for their interaction with PEX7 This allowed us to generate a prediction algorithm that identified functional PTS2 signals and a novel peroxisomal protein demonstrating the relevance of the identified criteria
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