A NOVEL HISTIDINE KINASE INHIBITOR REGULATING DEVELOPMENT IN BACILLUS-SUBTILIS

Kinase A is the sensor histidine kinase responsible for processing pos texponential phase information and providing phosphate input to the ph osphorelay that activates developmental transcription via phosphorylat ed Spo0A. A protein inhibitor, KipI, of kinase A was discovered encode d in an operon of genes of unknown function but regulated by the avail ability of fixed nitrogen. KipI is a potent inhibitor of the autophosp horylation reaction of kinase A but does not inhibit phosphate transfe r to the Spo0F response regulator once kinase A is phosphorylated. Kip I is an inhibitor of the catalytic domain of kinase A affecting the AT P/ADP reactions and not the phosphotransferase functions of this domai n. The inhibitory activity of KipI is counteracted by the product of a nother gene in the operon, KipA. This protein may bind to KipI, preven ting its function as an inhibitor of kinase A. KipI may be the first r epresentative of a new class of signal transduction inhibitors that fu nction by direct interaction with the catalytic domain of histidine ki nases to counteract signals influencing the ''sensor'' domain of such kinases. This inhibitor represents yet another way by which the phosph orelay signal transduction system is affected by negative regulators u nder the control of metabolic, environmental, or cell cycle influences antithetical to the initiation of developmental transcription.