Widespread atypical response regulator SecR governs bacterial growth on methylamines through the serine cycle.

Microbial utilization of methylamines (MAs) exerts profound effects on biogeochemical carbon cycles, yet the regulatory mechanisms enabling bacterial adaptation to fluctuating MAs availability remain elusive. Here, we report the discovery of previously unknown atypical response regulators, designated SecRs. They exhibit homology to RcsB from the two-component regulatory system but lack the conserved phosphorylation motif and a cognate kinase. SecRs serve as the gatekeeper of the serine cycle, an essential one-carbon assimilation pathway required for bacterial growth on MAs. Remarkably, Aminobacter sp. strain NyZ550 encodes both chromosomal and plasmid-borne secR homologs that differentially regulate identical targets encoding the serine cycle enzymes. Inactivation of secRs in strain NyZ550 abolishes its growth on MAs. Biochemical analyses demonstrate that purified SecRs form stable dimers capable of direct binding to the promoters of their own genes and those of the serine cycle genes, consequently activating transcription. SecR homologs are distributed among diverse terrestrial and marine methylotrophs, and frequently adjacent to the serine cycle genes in four distinct genomic arrangements, demonstrating that SecR-mediated regulation is conserved despite divergent evolutionary rearrangements of the serine cycle genes. The findings highlight the crucial role of SecR regulation in enabling microbial adaptation to biogeochemically important one-carbon compounds across diverse environments.