PAS/poly-HAMP signalling in Aer-2, a soluble haem-based sensor

Watts, Kylie J.; Taylor, Barry; Johnson, Mark S.

doi:10.1111/j.1365-2958.2010.07477.x

Cited by 45 publications

(89 citation statements)

References 70 publications

(111 reference statements)

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“…HAMP1 is also largely dispensable for Aer2 function (4). In contrast, N-terminal HAMP2-3, and C-terminal HAMP4-5, each form integrated di-HAMP units that are indispensable for Aer2 function (4,19). The HAMP1 and HAMP2 structures represent signal-on and signal-off states, respectively (18), lending support to the hypothesis that poly-HAMP chains relay signals by interconverting HAMP signaling states along the HAMP chain.…”

mentioning

confidence: 68%

“…The Aer2 gas response is initiated in the PAS (Per-ARNT-Sim) domain, which itself binds pentacoordinate b-type heme (4). PAS domains are common sensing and signaling domains in nature.…”

mentioning

confidence: 99%

“…Those structures show that HAMP1 is separated from HAMP2-3 by a helical extension (18,19). HAMP1 is also largely dispensable for Aer2 function (4). In contrast, N-terminal HAMP2-3, and C-terminal HAMP4-5, each form integrated di-HAMP units that are indispensable for Aer2 function (4,19).…”

mentioning

confidence: 99%

“…Based on experimental evidence, our current signaling model for Aer2 includes the following features: Aer2 PAS-heme binds O 2 , generating a conformational signal that is transmitted to the PAS I␤ strand (4,13,14). N-terminal HAMP2-3 structures do not transmit signals but function to stabilize the PAS signaling state by altering their conformations in response to PAS ligand binding (4,18).…”

mentioning

confidence: 99%

“…N-terminal HAMP2-3 structures do not transmit signals but function to stabilize the PAS signaling state by altering their conformations in response to PAS ligand binding (4,18). The PAS conformational signal is transmitted to C-terminal HAMP4-5, which together function as a unit to inhibit signaling from the kinase control module (4).…”

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confidence: 99%

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Gas Sensing and Signaling in the PAS-Heme Domain of the Pseudomonas aeruginosa Aer2 Receptor

et al. 2017

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The Aer2 chemoreceptor from Pseudomonas aeruginosa contains a PAS sensing domain that coordinates b-type heme and signals in response to the binding of O 2 , CO, or NO. PAS-heme structures suggest that Aer2 uniquely coordinates heme via a His residue on a 3 10 helix (H234 on E), stabilizes O 2 binding via a Trp residue (W283), and signals via both W283 and an adjacent Leu residue (L264). Ligand binding may displace L264 and reorient W283 for hydrogen bonding to the ligand. Here, we clarified the mechanisms by which Aer2-PAS binds heme, regulates ligand binding, and initiates conformational signaling. H234 coordinated heme, but additional hydrophobic residues in the heme cleft were also critical for stable heme binding. O 2 appeared to be the native Aer2 ligand (dissociation constant [K d ] of 16 M). With one exception, mutants that bound O 2 could signal, whereas many mutants that bound CO could not. W283 stabilized O 2 binding but not CO binding, and it was required for signal initiation; W283 mutants that could not stabilize O 2 were rapidly oxidized to Fe(III). W283F was the only Trp mutant that bound O 2 with wildtype affinity. The size and nature of residue 264 was important for gas binding and signaling: L264W blocked O 2 binding, L264A and L264G caused O 2 -mediated oxidation, and L264K formed a hexacoordinate heme. Our data suggest that when O 2 binds to Aer2, L264 moves concomitantly with W283 to initiate the conformational signal. The signal then propagates from the PAS domain to regulate the C-terminal HAMP and kinase control domains, ultimately modulating a cellular response.IMPORTANCE Pseudomonas aeruginosa is a ubiquitous environmental bacterium and opportunistic pathogen that infects multiple body sites, including the lungs of cystic fibrosis patients. P. aeruginosa senses and responds to its environment via four chemosensory systems. Three of these systems regulate biofilm formation, twitching motility, and chemotaxis. The role of the fourth system, Che2, is unclear but has been implicated in virulence. The Che2 system contains a chemoreceptor called Aer2, which contains a PAS sensing domain that binds heme and senses oxygen. Here, we show that Aer2 uses unprecedented mechanisms to bind O 2 and initiate signaling. These studies provide both the first functional corroboration of the Aer2-PAS signaling mechanism previously proposed from structure as well as a signaling model for Aer2-PAS receptors.KEYWORDS chemoreceptor, PAS domain, signal transduction, Pseudomonas aeruginosa, heme, oxygen P seudomonas aeruginosa is a common environmental bacterium and a significant cause of opportunistic human disease. It survives in complex environments with the aid of 26 chemoreceptors and four chemosensory systems that collectively sense environmental conditions and modify bacterial behavior. The roles of three of these chemosensory systems are known: one modulates type IV pili production and twitching motility (Pil-Chp system), another controls biofilm formation (Wsp system), and a third

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mentioning

confidence: 68%

“…The Aer2 gas response is initiated in the PAS (Per-ARNT-Sim) domain, which itself binds pentacoordinate b-type heme (4). PAS domains are common sensing and signaling domains in nature.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Gas Sensing and Signaling in the PAS-Heme Domain of the Pseudomonas aeruginosa Aer2 Receptor

et al. 2017

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AlphaFold2 captures the conformational landscape of the HAMP signaling domain

Winski,

Ludwiczak,

Orlowska

et al. 2023

Protein Science

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In this study, we present a conformational landscape of 5000 AlphaFold2 models of the Histidine kinases, Adenyl cyclases, Methyl‐accepting proteins and Phosphatases (HAMP) domain, a short helical bundle that transduces signals from sensors to effectors in two‐component signaling proteins such as sensory histidine kinases and chemoreceptors. The landscape reveals the conformational variability of the HAMP domain, including rotations, shifts, displacements, and tilts of helices, many combinations of which have not been observed in experimental structures. HAMP domains belonging to a single family tend to occupy a defined region of the landscape, even when their sequence similarity is low, suggesting that individual HAMP families have evolved to operate in a specific conformational range. The functional importance of this structural conservation is illustrated by poly‐HAMP arrays, in which HAMP domains from families with opposite conformational preferences alternate, consistent with the rotational model of signal transduction. The only poly‐HAMP arrays that violate this rule are predicted to be of recent evolutionary origin and structurally unstable. Finally, we identify a family of HAMP domains that are likely to be dynamic due to the presence of a conserved pi‐helical bulge. All code associated with this work, including a tool for rapid sequence‐based prediction of the rotational state in HAMP domains, is deposited at https://github.com/labstructbioinf/HAMPpred.

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The Dos Family of Globin-Related Sensors Using PAS Domains to Accommodate Haem Acting as the Active Site for Sensing External Signals

Aono

2013

Advances in Microbial Physiology

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PAS/poly-HAMP signalling in Aer-2, a soluble haem-based sensor

Cited by 45 publications

References 70 publications

Gas Sensing and Signaling in the PAS-Heme Domain of the Pseudomonas aeruginosa Aer2 Receptor

Gas Sensing and Signaling in the PAS-Heme Domain of the Pseudomonas aeruginosa Aer2 Receptor

AlphaFold2 captures the conformational landscape of the HAMP signaling domain

The Dos Family of Globin-Related Sensors Using PAS Domains to Accommodate Haem Acting as the Active Site for Sensing External Signals

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