Hidden localization motifs: naturally occurring peroxisomal targeting signals in non-peroxisomal proteins.
BACKGROUND
Can sequence segments coding for subcellular targeting or for posttranslational modifications occur in proteins that are not substrates in either of these processes? Although considerable effort has been invested in achieving low false-positive prediction rates, even accurate sequence-analysis tools for the recognition of these motifs generate a small but noticeable number of protein hits that lack the appropriate biological context but cannot be rationalized as false positives.


RESULTS
We show that the carboxyl termini of a set of definitely non-peroxisomal proteins with predicted peroxisomal targeting signals interact with the peroxisomal matrix protein receptor peroxin 5 (PEX5) in a yeast two-hybrid test. Moreover, we show that examples of these proteins - chicken lysozyme, human tyrosinase and the yeast mitochondrial ribosomal protein L2 (encoded by MRP7) - are imported into peroxisomes in vivo if their original sorting signals are disguised. We also show that even prokaryotic proteins can contain peroxisomal targeting sequences.


CONCLUSIONS
Thus, functional localization signals can evolve in unrelated protein sequences as a result of neutral mutations, and subcellular targeting is hierarchically organized, with signal accessibility playing a decisive role. The occurrence of silent functional motifs in unrelated proteins is important for the development of sequence-based function prediction tools and the interpretation of their results. Silent functional signals have the potential to acquire importance in future evolutionary scenarios and in pathological conditions.
Neuberger
Georg
G
Research Institute of Molecular Pathology (IMP), Dr Bohr-Gasse 7, A-1030 Vienna, Austria. neuberger@imp.univie.ac.at <neuberger@imp.univie.ac.at>
Kunze
Markus
M
Eisenhaber
Frank
F
Berger
Johannes
J
Hartig
Andreas
A
Brocard
Cecile
C
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002645:Chickens; D005656:Fungal Proteins / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000737:chemistry / Q000378:metabolism; D009113:Muramidase / Q000737:chemistry / Q000378:metabolism; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020675:Peroxisomes / Q000378:metabolism*; D021382:Protein Sorting Signals; D021381:Protein Transport; D012269:Ribosomal Proteins / Q000737:chemistry / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D005656:Fungal Proteins; C058594:MRP7 protein, S cerevisiae; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C499509:PEX5 protein, S cerevisiae; D000074435:Peroxisome-Targeting Signal 1 Receptor; D021382:Protein Sorting Signals; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D014442:Monophenol Monooxygenase; D009113:Muramidase