UniProt functional annotation for P9WGK3



	UniProt functional annotation for P9WGK3

UniProt code: P9WGK3.

Organism: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).

Taxonomy: Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex.

Function: Member of the two-component regulatory system DevR/DevS (DosR/DosS) involved in onset of the dormancy response (PubMed:12953092). Regulates an approximately 48-member regulon (PubMed:12953092, PubMed:11416222, PubMed:15033981, PubMed:18400743). Required for full induction of the DevR (DosR) regulon; acts later than DosT to positively regulate expression of the DevR regulon during adaptation to anaerobiosis (PubMed:19487478). Characterized as an oxygen sensor; O(2) acts as a switch, with O(2)-bound Fe(2+) protein inactive in autophosphorylation (PubMed:17371046, PubMed:17600145, PubMed:18975917, PubMed:19463006, PubMed:28977726). Has also been suggested to act as a redox sensor, or perhaps as a dual oxygen/redox sensor (PubMed:17609369). Autophosphorylates under anaerobic but not aerobic conditions, binding of NO or CO does not dramatically change the level of autophosphorylation of Fe(2+) protein, binding of O(2) inactivates kinase activity (PubMed:17600145, PubMed:18975917, PubMed:27235395). Binds O(2), NO, CO (PubMed:17371046, PubMed:17609369, PubMed:17600145, PubMed:18975917, PubMed:27235395). It is probably reduced by flavin nucleotides such as FMN and FAD (PubMed:19276084). May be the primary sensor for CO (PubMed:18400743). Donates a phosphate group to transcriptional regulator DevR (DosR) (PubMed:15033981, PubMed:15073296, PubMed:28977726). {ECO:0000269|PubMed:11416222, ECO:0000269|PubMed:12953092, ECO:0000269|PubMed:15033981, ECO:0000269|PubMed:15073296, ECO:0000269|PubMed:17371046, ECO:0000269|PubMed:17600145, ECO:0000269|PubMed:17609369, ECO:0000269|PubMed:18400743, ECO:0000269|PubMed:18474359, ECO:0000269|PubMed:18975917, ECO:0000269|PubMed:19463006, ECO:0000269|PubMed:19487478, ECO:0000269|PubMed:27235395, ECO:0000269|PubMed:28977726}.

Catalytic activity: Reaction=ATP + protein L-histidine = ADP + protein N-phospho-L- histidine.; EC=2.7.13.3; Evidence={ECO:0000269|PubMed:15033981};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:15073296, ECO:0000269|PubMed:17600145}; Note=Mn(2+) will also substitute in autophosphorylation assays, while Ca(2+) is a poor substitute (PubMed:17600145). {ECO:0000269|PubMed:17600145};

Cofactor: Name=heme; Xref=ChEBI:CHEBI:30413; Evidence={ECO:0000269|PubMed:16213520, ECO:0000269|PubMed:17371046, ECO:0000269|PubMed:17600145, ECO:0000269|PubMed:19463006, ECO:0000269|PubMed:21536032, ECO:0000269|PubMed:27729224}; Note=Binds 1 heme group per monomer (PubMed:16213520, PubMed:17371046, PubMed:17600145, PubMed:21536032, PubMed:27729224). {ECO:0000269|PubMed:16213520, ECO:0000269|PubMed:17371046, ECO:0000269|PubMed:17600145, ECO:0000269|PubMed:21536032, ECO:0000269|PubMed:27729224};

Biophysicochemical properties: Kinetic parameters: KM=73 uM for ATP for autophosphorylation by deoxy-DevS {ECO:0000269|PubMed:17600145};

Subunit: The isolated histidine kinase core (HKC, residues 386-578) is a dimer and autophosphorylates, suggesting the protein may function as a homodimer (PubMed:23486471). {ECO:0000269|PubMed:23486471}.

Subcellular location: Cytoplasm {ECO:0000305|PubMed:16213520, ECO:0000305|PubMed:17600145}.

Induction: A member of the dormancy regulon, expression is controlled by devR (PubMed:12953092, PubMed:19487478). Induced in response to reduced oxygen tension (hypoxia) (PubMed:11416222, PubMed:12953092, PubMed:19487478). Induced in response to low levels of nitric oxide (NO) and carbon monoxide (CO) (PubMed:12953092, PubMed:18400743). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Member of the Rv3134c-devR-devS operon (PubMed:10970762). {ECO:0000269|PubMed:10970762, ECO:0000269|PubMed:11416222, ECO:0000269|PubMed:12953092, ECO:0000269|PubMed:18400743, ECO:0000269|PubMed:19487478}.

Domain: The first GAF domain protects the heme moiety from auto- oxidation, contributing to the full-length protein's very long half- life (more than 36 hours in buffers without transition metals) (PubMed:19463006). The isolated ATP-binding subdomain (residues 454- 578) crystallized in a closed form that is unable to bind ATP, suggesting that ATP-binding requires conformational changes in this loop region; in this closed conformation it binds a zinc atom (PubMed:23486471). The isolated histidine kinase core (HKC, residues 386-578) both autophosphorylates and phosphorylates the isolated histidine acceptor subdomain (residues 386-452) (PubMed:23486471). The relative arrangements of the 2 subdomains of the HKC may control not only kinase activity but exposure of the ATP binding site (PubMed:23486471). {ECO:0000269|PubMed:19463006, ECO:0000269|PubMed:23486471}.

Disruption phenotype: Cells lacking this gene show no changes in gene induction following hypoxia, or exposure to NO or CO (PubMed:11416222, PubMed:15033981, PubMed:18474359). Another publication shows a severely attenuated response to CO (PubMed:18400743). Cells lacking both this gene and DosT have no response to hypoxia, or exposure to NO or CO showing both proteins are required for the hypoxic, NO and CO responses (PubMed:15033981). 95% decreased induction of the DevR (DosR) regulon during anaerobic growth, 50% decreased induction of the DevR regulon upon exposure to NO during aerobic growth (PubMed:19487478). {ECO:0000269|PubMed:11416222, ECO:0000269|PubMed:15033981, ECO:0000269|PubMed:18400743, ECO:0000269|PubMed:18474359, ECO:0000269|PubMed:19487478}.

Miscellaneous: Was identified as a high-confidence drug target. {ECO:0000305|PubMed:19099550}.

Miscellaneous: A tyrosine residue (Tyr-171) is required for discrimination between bound gaseous ligands (PubMed:18975917). The Tyr is part of a probable hydrogen bonding network which includes Glu-87, His-89 and Arg-204 that is probably also important for signaling to the kinase domain (PubMed:19276084, PubMed:27235395). {ECO:0000269|PubMed:18975917, ECO:0000305|PubMed:19276084, ECO:0000305|PubMed:27235395}.

Miscellaneous: The dev nomenclature derives from the increased expression (differentially expressed in virulent strain, dev) of these genes in virulent H37Rv versus avirulent H37Ra. The dos nomenclature derives from experiments in M.bovis showing the same genes are essential for dormancy survival. {ECO:0000305|PubMed:25002970}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
Taxonomy:		Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex.



Function:		Member of the two-component regulatory system DevR/DevS (DosR/DosS) involved in onset of the dormancy response (PubMed:12953092). Regulates an approximately 48-member regulon (PubMed:12953092, PubMed:11416222, PubMed:15033981, PubMed:18400743). Required for full induction of the DevR (DosR) regulon; acts later than DosT to positively regulate expression of the DevR regulon during adaptation to anaerobiosis (PubMed:19487478). Characterized as an oxygen sensor; O(2) acts as a switch, with O(2)-bound Fe(2+) protein inactive in autophosphorylation (PubMed:17371046, PubMed:17600145, PubMed:18975917, PubMed:19463006, PubMed:28977726). Has also been suggested to act as a redox sensor, or perhaps as a dual oxygen/redox sensor (PubMed:17609369). Autophosphorylates under anaerobic but not aerobic conditions, binding of NO or CO does not dramatically change the level of autophosphorylation of Fe(2+) protein, binding of O(2) inactivates kinase activity (PubMed:17600145, PubMed:18975917, PubMed:27235395). Binds O(2), NO, CO (PubMed:17371046, PubMed:17609369, PubMed:17600145, PubMed:18975917, PubMed:27235395). It is probably reduced by flavin nucleotides such as FMN and FAD (PubMed:19276084). May be the primary sensor for CO (PubMed:18400743). Donates a phosphate group to transcriptional regulator DevR (DosR) (PubMed:15033981, PubMed:15073296, PubMed:28977726). {ECO:0000269\|PubMed:11416222, ECO:0000269\|PubMed:12953092, ECO:0000269\|PubMed:15033981, ECO:0000269\|PubMed:15073296, ECO:0000269\|PubMed:17371046, ECO:0000269\|PubMed:17600145, ECO:0000269\|PubMed:17609369, ECO:0000269\|PubMed:18400743, ECO:0000269\|PubMed:18474359, ECO:0000269\|PubMed:18975917, ECO:0000269\|PubMed:19463006, ECO:0000269\|PubMed:19487478, ECO:0000269\|PubMed:27235395, ECO:0000269\|PubMed:28977726}.


Catalytic activity:		Reaction=ATP + protein L-histidine = ADP + protein N-phospho-L- histidine.; EC=2.7.13.3; Evidence={ECO:0000269\|PubMed:15033981};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:15073296, ECO:0000269\|PubMed:17600145}; Note=Mn(2+) will also substitute in autophosphorylation assays, while Ca(2+) is a poor substitute (PubMed:17600145). {ECO:0000269\|PubMed:17600145};
Cofactor:		Name=heme; Xref=ChEBI:CHEBI:30413; Evidence={ECO:0000269\|PubMed:16213520, ECO:0000269\|PubMed:17371046, ECO:0000269\|PubMed:17600145, ECO:0000269\|PubMed:19463006, ECO:0000269\|PubMed:21536032, ECO:0000269\|PubMed:27729224}; Note=Binds 1 heme group per monomer (PubMed:16213520, PubMed:17371046, PubMed:17600145, PubMed:21536032, PubMed:27729224). {ECO:0000269\|PubMed:16213520, ECO:0000269\|PubMed:17371046, ECO:0000269\|PubMed:17600145, ECO:0000269\|PubMed:21536032, ECO:0000269\|PubMed:27729224};
Biophysicochemical properties:		Kinetic parameters: KM=73 uM for ATP for autophosphorylation by deoxy-DevS {ECO:0000269\|PubMed:17600145};
Subunit:		The isolated histidine kinase core (HKC, residues 386-578) is a dimer and autophosphorylates, suggesting the protein may function as a homodimer (PubMed:23486471). {ECO:0000269\|PubMed:23486471}.
Subcellular location:		Cytoplasm {ECO:0000305\|PubMed:16213520, ECO:0000305\|PubMed:17600145}.
Induction:		A member of the dormancy regulon, expression is controlled by devR (PubMed:12953092, PubMed:19487478). Induced in response to reduced oxygen tension (hypoxia) (PubMed:11416222, PubMed:12953092, PubMed:19487478). Induced in response to low levels of nitric oxide (NO) and carbon monoxide (CO) (PubMed:12953092, PubMed:18400743). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Member of the Rv3134c-devR-devS operon (PubMed:10970762). {ECO:0000269\|PubMed:10970762, ECO:0000269\|PubMed:11416222, ECO:0000269\|PubMed:12953092, ECO:0000269\|PubMed:18400743, ECO:0000269\|PubMed:19487478}.
Domain:		The first GAF domain protects the heme moiety from auto- oxidation, contributing to the full-length protein's very long half- life (more than 36 hours in buffers without transition metals) (PubMed:19463006). The isolated ATP-binding subdomain (residues 454- 578) crystallized in a closed form that is unable to bind ATP, suggesting that ATP-binding requires conformational changes in this loop region; in this closed conformation it binds a zinc atom (PubMed:23486471). The isolated histidine kinase core (HKC, residues 386-578) both autophosphorylates and phosphorylates the isolated histidine acceptor subdomain (residues 386-452) (PubMed:23486471). The relative arrangements of the 2 subdomains of the HKC may control not only kinase activity but exposure of the ATP binding site (PubMed:23486471). {ECO:0000269\|PubMed:19463006, ECO:0000269\|PubMed:23486471}.
Disruption phenotype:		Cells lacking this gene show no changes in gene induction following hypoxia, or exposure to NO or CO (PubMed:11416222, PubMed:15033981, PubMed:18474359). Another publication shows a severely attenuated response to CO (PubMed:18400743). Cells lacking both this gene and DosT have no response to hypoxia, or exposure to NO or CO showing both proteins are required for the hypoxic, NO and CO responses (PubMed:15033981). 95% decreased induction of the DevR (DosR) regulon during anaerobic growth, 50% decreased induction of the DevR regulon upon exposure to NO during aerobic growth (PubMed:19487478). {ECO:0000269\|PubMed:11416222, ECO:0000269\|PubMed:15033981, ECO:0000269\|PubMed:18400743, ECO:0000269\|PubMed:18474359, ECO:0000269\|PubMed:19487478}.
Miscellaneous:		Was identified as a high-confidence drug target. {ECO:0000305\|PubMed:19099550}.
Miscellaneous:		A tyrosine residue (Tyr-171) is required for discrimination between bound gaseous ligands (PubMed:18975917). The Tyr is part of a probable hydrogen bonding network which includes Glu-87, His-89 and Arg-204 that is probably also important for signaling to the kinase domain (PubMed:19276084, PubMed:27235395). {ECO:0000269\|PubMed:18975917, ECO:0000305\|PubMed:19276084, ECO:0000305\|PubMed:27235395}.
Miscellaneous:		The dev nomenclature derives from the increased expression (differentially expressed in virulent strain, dev) of these genes in virulent H37Rv versus avirulent H37Ra. The dos nomenclature derives from experiments in M.bovis showing the same genes are essential for dormancy survival. {ECO:0000305\|PubMed:25002970}.