title: Structural and functional diversity of the microbial kinome.
abstract: The eukaryotic protein kinase (ePK) domain mediates the majority of signaling and coordination of complex events in eukaryotes. By contrast, most bacterial signaling is thought to occur through structurally unrelated histidine kinases, though some ePK-like kinases (ELKs) and small molecule kinases are known in bacteria. Our analysis of the Global Ocean Sampling (GOS) dataset reveals that ELKs are as prevalent as histidine kinases and may play an equally important role in prokaryotic behavior. By combining GOS and public databases, we show that the ePK is just one subset of a diverse superfamily of enzymes built on a common protein kinase-like (PKL) fold. We explored this huge phylogenetic and functional space to cast light on the ancient evolution of this superfamily, its mechanistic core, and the structural basis for its observed diversity. We cataloged 27,677 ePKs and 18,699 ELKs, and classified them into 20 highly distinct families whose known members suggest regulatory functions. GOS data more than tripled the count of ELK sequences and enabled the discovery of novel families and classification and analysis of all ELKs. Comparison between and within families revealed ten key residues that are highly conserved across families. However, all but one of the ten residues has been eliminated in one family or another, indicating great functional plasticity. We show that loss of a catalytic lysine in two families is compensated by distinct mechanisms both involving other key motifs. This diverse superfamily serves as a model for further structural and functional analysis of enzyme evolution.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhai
authors.forename: J Craig
authors.initials: JC
authors.lastname: Venter
authors.forename: Gerard
authors.initials: G
authors.lastname: Manning
mesh_terms: D001419:Bacteria / Q000201:enzymology*; D010802:Phylogeny; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011494:Protein Kinases