The power of the small: the underestimated role of small proteins in bacterial and archaeal physiology

Small proteins encoded by small open-reading frames (sORFs) (≤70 aa) were overlooked for decades due to methodological reasons and are thus often missing in genome annotations. Novel detection methods such as ribosome profiling (Ribo-Seq) and mass spectrometry optimized for small proteins (peptidomics) have opened up a new field of interest and several catalogs of small proteins in bacteria and archaea have been recently reported. Many translated sORFs have been discovered in genomic locations previously thought to be noncoding, such as 5' or 3' untranslated regions or well-studied regulatory small RNAs (sRNAs). Even within longer ORFs, additional functional sORFs have been detected. Today, only a small proportion is characterized, but those small proteins indicate important and diverse functions in cellular physiology. Here, we summarize recently characterized small proteins involved in microbial metabolism.