{PDOC52090} {PS52090; H_NOX} {BEGIN} *********************************************************** * Heme-nitric oxide/oxygen binding (H-NOX) domain profile * *********************************************************** Heme-nitric oxide/oxygen binding (H-NOX) domains bind diatomic gaseous ligands for signal transduction in organisms spanning prokaryotic and eukaryotic kingdoms. In prokaryotes, H-NOX sensors function as both stand-alone proteins and as members of multidomain proteins, and respond to nitric oxide (NO), oxygen and potentially other ligands such as carbon monoxide (CO) to induce a signaling cascade. Obligate anaerobes use H-NOX domains to escape dioxygen as part of a methyl-accepting chemotaxis system while a variety of bacteria use stand-alone H-NOX proteins to sense NO and repress biofilm formation through lowering cyclic di-GMP levels. In the latter case, H-NOX proteins may participate in a two-component signaling cascade, inhibiting a histidine kinase that stimulates a cyclic di-GMP synthase, or by directly stimulating the phosphodiesterase activity, and inhibiting the cyclase activity, of a cyclic di-GMP synthase/phosphodiesterase fusion protein. In animals, H-NOX domains are part of soluble guanylyl cyclase (sGC) proteins that generally sense NO but may also sense oxygen, for example in the worm Caenorhabditis elegans where oxygen levels regulate foraging. Heterodimeric sGC is composed of two chains, alpha and beta, produced through gene duplication with each chain containing an N-terminal H-NOX domain, a central PAS (Per-ARNT-Sim) domain, a coiled-coil domain and a C-terminal cyclase domain (see ). The alpha H-NOX domain has lost the ability to bind heme and is best categorized as a pseudo H-NOX domain. By producing cGMP in response to NO binding, heterodimeric sGC regulates numerous physiological processes in animals, including blood pressure, wound healing, and memory formation, and is also emerging as antitumorigenic. The animal H-NOX domains were probably acquired through lateral transfer from a bacterial source [1,2,3,4,5,6,7,8]. The H-NOX domain of ~190 amino acids consists of seven alpha-helices, labeled alphaA-G, and one four-stranded antiparallel beta-sheet (strands beta1-4) (see ). The presence of a beta-sheet in the H-NOX structure distinguishes it from the all helical globin fold. The H-NOX domain includes a small N- terminal subdomain consisting of three of the helices and a large C-terminal subdomain consisting of four helices, the four-stranded beta sheet and the heme pocket. The heme cofactor is deeply buried between the two subdomains and the central iron is coordinated axially to a conserved His residue on alpha- helix F. Several structural features in the heme pocket of the unligated protein function to maintain the heme distorted from planarity. NO association severely weakens the iron-histidine bond, resulting in histidine dissociation and the formation of an activated five-coordinate, NO-bound heme. NO-induced scission of the heme-histidine bond elicits a pronounced conformational change in the protein as a result of structural rearrangements in the heme pocket that permit the heme to relax toward planarity. A nonheme metal coordination site occupied by zinc is limited predominantly to a select group of H-NOX proteins from gammaproteobacteria. Zinc coordination in H-NOX proteins serves a structural role, a feature common to sites of tetrahedral zinc coordination, and links the beta3-beta4 loop to helix alphaG within the proximal subdomain of zinc-binding H-NOX proteins [3,4,5,6,7]. H-NOX domains have also been named heme-NO-binding (H-NOB) domains, but the term H-NOX should be prefered to encompass more broadly their ligand-binding properties [1,2,3,4]. Some proteins known to contain a H-NOX domain are listed below: - Animal NO receptor soluble guanylate cyclase (sGC), which is activated by NO to catalyze the cyclization of 5'-guanosine triphosphate (GTP) to 3',5'- cyclic guanosine monophosphate (cGMP). - Shewanella oneidensis NO-binding heme-dependent sensor protein SO_2144, has high homology and similar ligand-binding properties to sGC. - Shewanella woodyi heme NO binding domain protein Swoo_2751. - Nostoc punctiforme Heme NO binding domain protein Npun_R4836. - Caldanaerobacter subterraneus subsp. tengcongensis methyl-accepting chemotaxis protein Tar4, contains an oxygen-binding H-NOX domain. - Vibrio cholerae guanylate cyclase-related protein VCA0720, encoded in a histidine kinase-containing operon. The profile we developed covers the entire H-NOX domain. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Last update: February 2026 / First entry. [ 1] Iyer L.M., Anantharaman V., Aravind L. "Ancient conserved domains shared by animal soluble guanylyl cyclases and bacterial signaling proteins." BMC Genomics 4:5-5(2003). PubMed=12590654; DOI=10.1186/1471-2164-4-5 [ 2] Karow D.S., Pan D., Tran R., Pellicena P., Presley A., Mathies R.A., Marletta M.A. "Spectroscopic characterization of the soluble guanylate cyclase-like heme domains from Vibrio cholerae and Thermoanaerobacter tengcongensis." Biochemistry 43:10203-10211(2004). PubMed=15287748; DOI=10.1021/bi049374l [ 3] Pellicena P., Karow D.S., Boon E.M., Marletta M.A., Kuriyan J. "Crystal structure of an oxygen-binding heme domain related to soluble guanylate cyclases." Proc. Natl. Acad. Sci. U. S. A. 101:12854-12859(2004). PubMed=15326296; DOI=10.1073/pnas.0405188101 [ 4] Cary S.P.L., Winger J.A., Derbyshire E.R., Marletta M.A. "Nitric oxide signaling: no longer simply on or off." Trends. Biochem. Sci. 31:231-239(2006). PubMed=16530415; DOI=10.1016/j.tibs.2006.02.003 [ 5] Plate L., Marletta M.A. "Nitric oxide-sensing H-NOX proteins govern bacterial communal behavior." Trends. Biochem. Sci. 38:566-575(2013). PubMed=24113192; DOI=10.1016/j.tibs.2013.08.008 [ 6] Herzik M.A. Jr., Jonnalagadda R., Kuriyan J., Marletta M.A. "Structural insights into the role of iron-histidine bond cleavage in nitric oxide-induced activation of H-NOX gas sensor proteins." Proc. Natl. Acad. Sci. U. S. A. 111:E4156-E4164(2014). PubMed=25253889; DOI=10.1073/pnas.1416936111 [ 7] Chen C.-Y., Lee W., Renhowe P.A., Jung J., Montfort W.R. "Solution structures of the Shewanella woodyi H-NOX protein in the presence and absence of soluble guanylyl cyclase stimulator IWP-051." Protein. Sci. 30:448-463(2021). PubMed=33236796; DOI=10.1002/pro.4005 [ 8] Chasapi S.A., Argyriou A.I., Spyroulias G.A. "Backbone and side chain NMR assignment of the heme-nitric oxide/oxygen binding (H-NOX) domain from Nostoc punctiforme." Biomol. NMR. Assign. 16:379-384(2022). PubMed=36066818; DOI=10.1007/s12104-022-10107-1 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}