Regulatory potential, phyletic distribution and evolution of ancient, intracellular small-molecule-binding domains

Central cellular functions such as metabolism, solute transport and signal transduction are regulated, in part, via binding of small. molecules by spe cialized domains. Using sensitive methods for sequence profile analysis and protein structure comparison, we exhaustively surveyed the protein sets fr om completely sequenced genomes for all occurrences of 21 intracellular sma ll-molecule-binding domains (SMBDs) that are represented in at least two of the three major divisions of life (bacteria, archaea and eukaryotes). Thes e included previously characterized domains such as PAS, GAF, ACT and ferre doxins, as well as three newly predicted SMBDs, namely the 4-vinyl reductas e (4VR) domain, the NIFX domain and the S-histidines (3H) domain. Although there are only a limited number of different superfamilies of these ancient SMBDs, they are present in numerous distinct proteins combined with variou s enzymatic, transport and signal-transducing domains. Most of the SMBDs sh ow considerable evolutionary mobility and are involved in the generation of many lineage-specific domain architectures. Frequent re-invention of analo gous architectures involving functionally related, but not homologous, doma ins was detected, such as, fusion of different SMBDs to several types of DN A-binding domains to form diverse transcription regulators in prokaryotes a nd eukaryotes. This is suggestive of similar selective forces affecting the diverse SMBDs and resulting in the formation of multidomain proteins that fit a limited number of functional stereotypes. Using the "guilt by associa tion approach", the identification of SMBDs allowed prediction of functions and mode of regulation for a variety of previously uncharacterized protein s. (C) 2001 Academic Press.