Chapter 78 - Histidine Kinases in Two-Component Signaling Pathways

Abstract

The main purpose of this chapter is to summarize the current understanding of histidine kinases: their domain organization, evolutionary diversity, structural architecture, and novel functional properties. Histidine kinases are found in most bacteria, archaea, and lower eukaryotic species such as slime molds, fungi, and plants where they function in two-component signal transduction pathways. The canonical two-component system (TCS) utilizes two distinctive signaling proteins, a membrane-bound sensor histidine kinase (HK) and a cytoplasmic response regulator (RR) protein. Signal transduction pathways involving a His-to-Asp phosphorelay regulate important cellular processes such as nutrient acquisition, adaptation to environmental stress, cell motility, development, virulence, and intercellular communication. Most histidine kinases are membrane-bound dimeric proteins with an N-terminal periplasmic sensory domain. However, some transmembrane HKs lack an extracellular sensory domain and presumably are responsive to membrane-associated signals. In addition, there are also HKs that are cytoplasmic proteins harboring sensory domains that detect intracellular changes. The core ATP-binding catalytic domains of HKs are recognizable due to a conserved set of sequence motifs designated as N, G1, F, and G2 boxes. These conserved sequences are essential for Mg2+- and ATP-binding. The mechanism of signal propagation of HKs remains elusive. Transmembrane signaling across biological membranes involves participation of the HK transmembrane helices. In the dimeric state, these are believed to be symmetrically arranged four-helix bundles. In general, sensory domains of HKs are highly divergent from one another in terms of sequence variability—a feature reflective of the wide range of stimuli that HKs are responsive to.