Unexpected Diversity of Signal Peptides in Prokaryotes

ABSTRACT Signal peptides are a cornerstone mechanism for cellular protein localization, yet until now experimental determina-tion of signal peptides has come from only a narrow taxonomic sampling. As a result, the dominant view is that Sec-cleaved sig-nal peptides in prokaryotes are defined by a canonical AxAmotif. Although other residues are permitted in the motif, alanine is by far the most common. Here we broadly examine proteomics data to reveal the signal peptide sequences for 32 bacterial and archaeal organisms from nine phyla and demonstrate that this alanine preference is not universal. Discoveries include funda-mentally distinct signal peptide motifs from Alphaproteobacteria, Spirochaetes, Thermotogae and Euryarchaeota. In these novel motifs, alanine is no longer the dominant residue but has been replaced in a different way for each taxon. Surprisingly, divergent motifs correlate with a proteome-wide reduction in alanine. Computational analyses of ~1,500 genomes reveal numerous major evolutionary clades which have replaced the canonical signal peptide sequence with novel motifs. IMPORTANCE This article replaces a widely held general model with a more detailed model describing phylogenetically correlate