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6  structures 832  species 0  interactions 4330  sequences 422  architectures

Family: HWE_HK (PF07536)

Summary: HWE histidine kinase

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HWE histidine kinase Provide feedback

Two-component systems, consisting of a histidine kinase and a cognate response regulator protein, represent the best-known apparatus for transducing external cues into a physiological response in bacteria. The HWE domain is found in a subset of two-component system kinases, belonging to the same superfamily as PF00512 [1] and PF07568 [2]. The family was defined by [1] the presence of a highly conserved H residue in the kinase domain and a WxE motif in a C-terminal ATPase domain that is related to PF02518. It has been demonstrated to show structural and functional correlation with PF07568 [2]. These proteins are found in a variety of alpha- and gamma- proteobacteria, with significant enrichment in the rhizobia.

Literature references

  1. Karniol B, Vierstra RD; , J Bacteriol 2004;186:445-453.: The HWE Histidine Kinases, a New Family of Bacterial Two-Component Sensor Kinases with Potentially Diverse Roles in Environmental Signaling. PUBMED:14702314 EPMC:14702314

  2. Herrou J, Crosson S, Fiebig A;, Curr Opin Microbiol. 2017;36:47-54.: Structure and function of HWE/HisKA2-family sensor histidine kinases. PUBMED:28193573 EPMC:28193573

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR011102

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions [ PUBMED:16176121 ]. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk [ PUBMED:18076326 ]. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more [ PUBMED:12372152 ]. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) [ PUBMED:10966457 ]. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [ PUBMED:11934609 , PUBMED:11489844 ].

Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms [ PUBMED:8868347 , PUBMED:11406410 ]. Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation [ PUBMED:10426948 ], and CheA, which plays a central role in the chemotaxis system [ PUBMED:9989504 ]. Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water [ PUBMED:11145881 ]. The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

HKs can be roughly divided into two classes: orthodox and hybrid kinases [ PUBMED:8029829 , PUBMED:1482126 ]. Most orthodox HKs, typified by the Escherichia coli EnvZ protein, function as periplasmic membrane receptors and have a signal peptide and transmembrane segment(s) that separate the protein into a periplasmic N-terminal sensing domain and a highly conserved cytoplasmic C-terminal kinase core. Members of this family, however, have an integral membrane sensor domain. Not all orthodox kinases are membrane bound, e.g., the nitrogen regulatory kinase NtrB (GlnL) is a soluble cytoplasmic HK [ PUBMED:10966457 ]. Hybrid kinases contain multiple phosphodonor and phosphoacceptor sites and use multi-step phospho-relay schemes instead of promoting a single phosphoryl transfer. In addition to the sensor domain and kinase core, they contain a CheY-like receiver domain and a His-containing phosphotransfer (HPt) domain.

The HWE domain is found in a subset of two-component system kinases, belonging to the same superfamily as INTERPRO [ PUBMED:14702314 ]. In [ PUBMED:14702314 ], the HWE family was defined by the presence of conserved a H residue and a WXE motifs and was limited to members of the proteobacteria. However, many homologues of this domain are lack the WXE motif. Furthermore, homologues are found in a wide range of Gram-positive and Gram-negative bacteria as well as in several archaea.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan His_Kinase_A (CL0025), which has the following description:

This is the dimerisation and phospho-acceptor domain of a sub-family of histidine kinases. It shares sequence similarity with Pfam:PF00512 and Pfam:PF07536. It is usually found adjacent to a C-terminal ATPase domain (Pfam:PF02518). This domain is found in a wide range of Bacteria and also several Archaea. It comprises one of the fundamental units of the two-component signal transduction system [2-7].

The clan contains the following 11 members:

H-kinase_dim HATPase_c HATPase_c_2 HATPase_c_3 HATPase_c_4 HATPase_c_5 HisKA HisKA_2 HisKA_3 HPTransfase HWE_HK


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: [1]
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Studholme DJ
Number in seed: 32
Number in full: 4330
Average length of the domain: 82.50 aa
Average identity of full alignment: 31 %
Average coverage of the sequence by the domain: 14.63 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.8 22.8
Trusted cut-off 22.8 22.8
Noise cut-off 22.7 22.7
Model length: 83
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HWE_HK domain has been found. There are 6 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A6X554 View 3D Structure Click here
Q2NCA3 View 3D Structure Click here
Q2YKK7 View 3D Structure Click here