Structure of a biological oxygen sensor: A new mechanism for heme-driven signal transduction

Gong, Weimin; Hao, Bing; Mansy, Sheref S.; González, Gonzalo; Gilles-Gonzalez, Marie Alda; Chan, Michael K.

doi:10.1073/pnas.95.26.15177

Cited by 374 publications

(495 citation statements)

References 43 publications

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“…This includes a five-stranded β-sheet and a long central helix (helical connector) generally linked to a bulge of three small helices. Following the nomenclature established for FixL (22) and generally adopted for PAS structures in the literature (Figure 2a), the N-terminal β-strands are referred to as Aβ and Bβ, followed by three small helices (Cα, Dα, and Eα), the helical connector (Fα), and the three C-terminal strands of the β-sheet (Gβ, Hβ, and Iβ).…”

Section: Choice Of the Template Structures And Alignmentmentioning

confidence: 99%

Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis

et al. 2006

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that is activated by a structurally diverse array of synthetic and natural chemicals, including toxic halogenated aromatic hydrocarbons such as 2, 3,7,. Analysis of the molecular events occurring in the AhR ligand binding and activation processes requires structural information on the AhR Per-Arnt-Sim (PAS) B-containing ligand binding domain, for which no experimentally determined structure has been reported. With the availability of extensive structural information on homologous PAS-containing proteins, a reliable model of the mouse AhR PAS B domain was developed by comparative modeling techniques. The PAS domain structures of the functionally related hypoxia-inducible factor 2α (HIF-2α) and AhR nuclear translocator (ARNT) proteins, which exhibit the highest degree of sequence identity and similarity with AhR, were chosen to develop a two-template model. To confirm the features of the modeled domain, the effects of point mutations in selected residue positions on both TCDD binding to the AhR and TCDD-dependent transformation and DNA binding were analyzed. Mutagenesis and functional analysis results are consistent with the proposed model and confirm that the cavity modeled in the interior of the domain is indeed involved in ligand binding. Moreover, the physicochemical characteristics of some residues and of their mutants, along with the effects of mutagenesis on TCDD and DNA binding, also suggest some key features that are required for ligand binding and activation of mAhR at a molecular level, thus providing a framework for further studies.The aryl hydrocarbon receptor (AhR) 1 is a basic helix-loop-helix (bHLH), PAS-(Per-ArntSim-) containing transcription factor which is present in numerous species and tissues and activates gene expression in a ligand-dependent manner (1-3). While the AhR can bind and be activated by a large number of structurally diverse chemicals (4-6), the highest affinity ligands include halogenated aromatic hydrocarbons (HAHs), such as 2, 3,7,8- NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2010 April 28. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript tetrachlorodibenzo-p-dioxin (TCDD, dioxin), and polycyclic aromatic hydrocarbons (PAHs), both widespread classes of environmental contaminants (4,7). Mechanistically, the inducing chemical diffuses across the plasma membrane and binds to the cytosolic AhR which exists as a multiprotein complex containing two molecules of hsp90 (a heat shock protein of 90 kDa), the X-associated protein 2 (XAP2), and the cochaperone p23 (8).Following ligand binding, the AhR is presumed to undergo a conformational change (9), exposing an N-terminal nuclear localization sequence that leads to translocation of the liganded AhR complex into the nucleus (10). Dissociation of the AhR from the protein complex and its dimerization with ARNT (AhR nuclear translocator) convert the AhR complex into its high-affinity ...

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Section: Choice Of the Template Structures And Alignmentmentioning

confidence: 99%

Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis

et al. 2006

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“…42, No. 25, 2003 7707 heme propionates, new polar interactions, and an outward push of the FG loop (8).…”

Section: How Does the G -2 Arginine Assist Binding Of O 2 And Cyanidementioning

confidence: 99%

“…It is conserved in all known FixL proteins, AxPDEA1, and EcDos (3,6,7). It is the only polar residue in the heme pockets of FixL proteins (8,9). In BjFixL, this arginine is at the start of the distal G strand, just after the end of the FG loop, and is thus well poised to communicate to the FG loop the changes triggered by binding of ligands ( Figure 1).…”

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confidence: 99%

A Distal Arginine in Oxygen-Sensing Heme-PAS Domains Is Essential to Ligand Binding, Signal Transduction, and Structure

et al. 2003

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To evaluate the contributions of the Gβ-2 arginine to signal transduction in oxygen-sensing heme-PAS domains, we replaced this residue with alanine in Bradyrhizobium japonicum FixL and examined the results on heme-domain structure, ligand binding, and kinase regulation. In the isolated R220A BjFixL heme-PAS domain, the iron−histidine bond was increased in length by 0.31 Å, the heme flattened even without a ligand, and the interaction of a presumed regulatory loop (the FG loop) with the helix of heme attachment was weakened. Binding of carbon monoxide was similar for ferrous BjFixL and R220A BjFixL. In contrast, the level of binding of oxygen was dramatically lower (K d ∼ 1.5 mM) for R220A BjFixL, and this was manifested as 60- and 3-fold lower on- and off-rate constants, respectively. Binding of cyanide followed the same pattern as binding of oxygen. The catalytic activity was 3−4-fold higher in the “on-state” unliganded forms of R220A BjFixL than in the corresponding BjFixL species. Cyanide regulation of this activity was strongly impaired, but some inhibition was nevertheless preserved. Carbon monoxide and nitric oxide regulation, although weak in BjFixL, were abolished from R220A BjFixL. We conclude that the Gβ-2 arginine assists in the binding of oxygen to BjFixL but does not accomplish this by stabilizing the oxy form. This arginine is not absolutely required for regulation, although it is important for shifting a pre-existing kinase equilibrium toward the inactive state on binding of regulatory ligands. These findings support a regulatory model in which the heme-PAS domain operates as an ensemble that couples to the kinase rather than a mechanism driven by a single central switch.

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“…In addition to their sensory functions, PAS domains have been reported to mediate protein-protein interactions (18). The PAS superfamily is characterized structurally by three helical segments flanking a five-stranded antiparallel ␤-sheet (19)(20)(21)(22)(23) (27)(28)(29); and (iv) FMN noncovalently bound to phototropin (9,12). Three crystal structures from the PAS-domain superfamily have been reported: the bacterial blue-light photosensor PYP (19,20), the heme-binding domain of the rhizobial oxygen sensor FixL (21,22), and the N-terminal domain of the human ether-a-gogo-related gene potassium channel (HERG; ref.…”

mentioning

confidence: 99%

Structure of a flavin-binding plant photoreceptor domain: Insights into light-mediated signal transduction

Crosson

Moffat

2001

Proc. Natl. Acad. Sci. U.S.A.

465

539

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Structure of a biological oxygen sensor: A new mechanism for heme-driven signal transduction

Cited by 374 publications

References 43 publications

Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis

Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis

A Distal Arginine in Oxygen-Sensing Heme-PAS Domains Is Essential to Ligand Binding, Signal Transduction, and Structure

Structure of a flavin-binding plant photoreceptor domain: Insights into light-mediated signal transduction

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