Assembly of the Transmembrane Domain of E. coli PhoQ Histidine Kinase: Implications for Signal Transduction from Molecular Simulations

Thomas Lemmin, Cinque S Soto, Graham Clinthorne, William F DeGrado and Matteo Dal Peraro

PLOS Computational Biology, 2013, vol. 9, issue 1, 1-11

Abstract: The PhoQP two-component system is a signaling complex essential for bacterial virulence and cationic antimicrobial peptide resistance. PhoQ is the histidine kinase chemoreceptor of this tandem machine and assembles in a homodimer conformation spanning the bacterial inner membrane. Currently, a full understanding of the PhoQ signal transduction is hindered by the lack of a complete atomistic structure. In this study, an atomistic model of the key transmembrane (TM) domain is assembled by using molecular simulations, guided by experimental cross-linking data. The formation of a polar pocket involving Asn202 in the lumen of the tetrameric TM bundle is crucial for the assembly and solvation of the domain. Moreover, a concerted displacement of the TM helices at the periplasmic side is found to modulate a rotation at the cytoplasmic end, supporting the transduction of the chemical signal through a combination of scissoring and rotational movement of the TM helices. Author Summary: Two-component systems (TCSs) are signaling complexes essential for bacterial survival and virulence. PhoQ is the histidine kinase chemoreceptor of the PhoQ-PhoP tandem machine that detects the concentration of cationic species at the inner membrane of Gram-negative bacteria. A full understanding of the PhoQ signal transduction mechanism is currently hindered by the lack of a complete atomistic structure. Here, by using molecular simulations integrated with cross-linking disulfide scanning data, we present the first structural model of the transmembrane (TM) portion of PhoQ from E. coli. Its structural and dynamic features induce a concerted displacement of the TM helices at the periplasmic side, which modulates a rotation at the cytoplasmic end. This supports the idea that signal transduction is promoted through a combination of scissoring and rotational movements of the TM helices. This complex mechanism is the key to understanding how the chemical stimuli sensed by the periplasmic sensor domain trigger, via the relay of the HAMP domain, the histidine auto-phosphorylation and kinase/phosphatase activity at the cytoplasmic end.

Date: 2013
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1002878

DOI: 10.1371/journal.pcbi.1002878

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