Mechanism of Regulation of Receptor Histidine Kinases

• Published in: Structure (London) 2012-01, Vol.20 (1), p.56-66
• Main Authors: Ferris, Hedda U., Dunin-Horkawicz, Stanislaw, Hornig, Nora, Hulko, Michael, Martin, Jörg, Schultz, Joachim E., Zeth, Kornelius, Lupas, Andrei N., Coles, Murray
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Bacterial Outer Membrane Proteins - chemistry; Bacterial Outer Membrane Proteins - metabolism; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - physiology; Catalytic Domain - genetics; Computational Biology; Crystallography, X-Ray; Escherichia coli Proteins - chemistry; Escherichia coli Proteins - metabolism; Histidine Kinase; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - physiology; Models, Molecular; Molecular Sequence Data; Multienzyme Complexes - chemistry; Multienzyme Complexes - metabolism; Nuclear Magnetic Resonance, Biomolecular; Protein Kinases - chemistry; Protein Kinases - genetics; Protein Kinases - physiology; Protein Structure, Tertiary; Signal Transduction - physiology
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2011.11.014

Bacterial transmembrane receptors regulate an intracellular catalytic output in response to extracellular sensory input. To investigate the conformational changes that relay the regulatory signal, we have studied the HAMP domain, a ubiquitous intracellular module connecting input to output domains. HAMP forms a parallel, dimeric, four-helical coiled coil, and rational substitutions in our model domain (Af1503 HAMP) induce a transition in its interhelical packing, characterized by axial rotation of all four helices (the gearbox signaling model). We now illustrate how these conformational changes are propagated to a downstream domain by fusing Af1503 HAMP variants to the DHp domain of EnvZ, a bacterial histidine kinase. Structures of wild-type and mutant constructs are correlated with ligand response in vivo, clearly associating them with distinct signaling states. We propose that altered recognition of the catalytic domain by DHp, rather than a shift in position of the phospho-accepting histidine, forms the basis for regulation of kinase activity. ► The HAMP and DHp domains of a histidine kinase communicate via rotational signals ► Rotation peaks at a conserved charged layer at the HAMP-DHp domain junction ► The position of the phospho-accepting histidine is not modulated during signaling ► The enzyme is regulated by specific recognition of the catalytic domain by DHp