|SMART accession number:||SM00389|
|Description:||DNA-binding factors that are involved in the transcriptional regulation of key developmental processes|
|Interpro abstract (IPR001356):||The homeobox domain or homeodomain was first identified in a number of drosophila homeotic and segmentation proteins, but is now known to be well-conserved in many other animals, including vertebrates [(PUBMED:2568852), (PUBMED:1357790), ]. Hox genes encode homeodomain-containing transcriptional regulators that operate differential genetic programs along the anterior-posterior axis of animal bodies [(PUBMED:12445403)]. The domain binds DNA through a helix-turn-helix (HTH) structure. The HTH motif is characterised by two alpha-helices, which make intimate contacts with the DNA and are joined by a short turn. The second helix binds to DNA via a number of hydrogen bonds and hydrophobic interactions, which occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA . The first helix helps to stabilise the structure. |
The motif is very similar in sequence and structure in a wide range of DNA-binding proteins (e.g., cro and repressor proteins, homeotic proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereo-chemical requirement for glycine in the turn which is needed to avoid steric interference of the beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, while for many of the homeotic and other DNA-binding proteins the requirement is relaxed.
|GO process:||regulation of transcription, DNA-dependent (GO:0006355)|
|GO function:||sequence-specific DNA binding (GO:0043565), sequence-specific DNA binding transcription factor activity (GO:0003700)|
Click on the following links for more information.
- Evolution (species in which this domain is found)
Click on to expand nodes. To display all proteins with a HOX domain in a specific node, click on it.
This tree shows only several representative species. The complete taxonomic breakdown of all proteins with HOX domain is also avaliable.
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Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes
- Cellular role (predicted cellular role)
Cellular role: transcription
Binding / catalysis: DNA-binding
- Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Aravind L, Koonin EV
- The U box is a modified RING finger - a common domain in ubiquitination.
- Curr Biol. 2000; 10: 1324-1324
- Vershon AK
- Protein interactions of homeodomain proteins.
- Curr Opin Biotechnol. 1996; 7: 392-6
- Display abstract
Homeodomain proteins are conserved DNA-binding factors that are involved in the transcriptional regulation of key developmental processes. Many homeodomain proteins require additional cofactors to bind with high affinity and specificity to their DNA sites. The recent structural determinations and biochemical analysis of several multimeric complexes have provided a better understanding of how protein interactions influence the DNA-binding activity of homeodomain proteins.
- Wolberger C
- Homeodomain interactions.
- Curr Opin Struct Biol. 1996; 6: 62-8
- Display abstract
Homeodomain proteins play key roles in development and gene regulation in eukaryotes. Past structural studies have focused on the binding of monomeric homeodomains to DNA, but two recent structures have revealed how homeodomains bind DNA as multimers. The structures of the Drosophila Paired homodimer and the yeast a1/alpha2 heterodimer bound to DNA, along with a high-resolution study of a Drosophila eve-DNA complex, have deepened our understanding of how homeodomains locate their DNA targets.
- Xu W, Rould MA, Jun S, Desplan C, Pabo CO
- Crystal structure of a paired domain-DNA complex at 2.5 A resolution reveals structural basis for Pax developmental mutations.
- Cell. 1995; 80: 639-50
- Display abstract
The 2.5 A resolution structure of a cocrystal containing the paired domain from the Drosophila paired (prd) protein and a 15 bp site shows structurally independent N-terminal and C-terminal subdomains. Each of these domains contains a helical region resembling the homeodomain and the Hin recombinase. The N-terminal domain makes extensive DNA contacts, using a novel beta turn motif that binds in the minor groove and a helix-turn-helix unit with a docking arrangement surprisingly similar to that of the lambda repressor. The C-terminal domain is not essential for prd binding and does not contact the optimized site. All known developmental missense mutations in the paired box of mammalian Pax genes map to the N-terminal subdomain, and most of them are found at the protein-DNA interface.
- Gehring WJ, Affolter M, Burglin T
- Homeodomain proteins.
- Annu Rev Biochem. 1994; 63: 487-526
- Gehring WJ et al.
- Homeodomain-DNA recognition.
- Cell. 1994; 78: 211-23
- Ghysen A
- Origins of segment periodicity.
- Nature. 1990; 344: 297-8
- Kissinger CR, Liu BS, Martin-Blanco E, Kornberg TB, Pabo CO
- Crystal structure of an engrailed homeodomain-DNA complex at 2.8 A resolution: a framework for understanding homeodomain-DNA interactions.
- Cell. 1990; 63: 579-90
- Display abstract
The crystal structure of a complex containing the engrailed homeodomain and a duplex DNA site has been determined at 2.8 A resolution and refined to a crystallographic R factor of 24.4%. In this complex, two separate regions of the 61 amino acid polypeptide contact a TAAT subsite. An N-terminal arm fits into the minor groove, and the side chains of Arg-3 and Arg-5 make contacts near the 5' end of this "core consensus" binding site. An alpha helix fits into the major groove, and the side chains of IIe-47 and Asn-51 contact base pairs near the 3' end of the TAAT site. This "recognition helix" is part of a structurally conserved helix-turn-helix unit, but these helices are longer than the corresponding helices in the lambda repressor, and the relationship between the helix-turn-helix unit and the DNA is significantly different.
- Landschulz WH, Johnson PF, McKnight SL
- The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins.
- Science. 1988; 240: 1759-64
- Display abstract
A 30-amino-acid segment of C/EBP, a newly discovered enhancer binding protein, shares notable sequence similarity with a segment of the cellular Myc transforming protein. Display of these respective amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns. The periodic array of at least four leucines was also noted in the sequences of the Fos and Jun transforming proteins, as well as that of the yeast gene regulatory protein, GCN4. The polypeptide segments containing these periodic arrays of leucine residues are proposed to exist in an alpha-helical conformation, and the leucine side chains extending from one alpha helix interdigitate with those displayed from a similar alpha helix of a second polypeptide, facilitating dimerization. This hypothetical structure is referred to as the "leucine zipper," and it may represent a characteristic property of a new category of DNA binding proteins.
- Disease (disease genes where sequence variants are found in this domain)
SwissProt sequences and OMIM curated human diseases associated with missense mutations within the HOX domain.
Protein Disease Homeobox expressed in ES cells 1 (Q9UBX0) (SMART) OMIM:601802: Septooptic dysplasia
Homeobox protein prophet of Pit-1 (O75360) (SMART) OMIM:601538: Pituitary hormone deficiency, combined Homeobox protein MSX-2 (P35548) (SMART) OMIM:123101: Craniosynostosis, type 2
OMIM:604757: Parietal foramina 1
OMIM:168500: Parietal foramina
Pituitary-specific positive transcription factor 1 (P28069) (SMART) OMIM:173110: Pituitary hormone deficiency, combined Homeobox protein SIX3 (O95343) (SMART) OMIM:157170: Holoprosencephaly-2
Homeobox protein Nkx-2.5 (P52952) (SMART) OMIM:600584: Atrial septal defect with atrioventricular conduction defects
Homeobox protein MSX-1 (P28360) (SMART) OMIM:142983: Hypodontia, autosomal dominant
OMIM:106600: Hypodontia with orofacial cleft
Homeobox protein aristaless-like 4 (Q9H161) (SMART) OMIM:168500: Parietal foramina
OMIM:605420: Parietal foramina 2
Cone-rod homeobox protein (O43186) (SMART) OMIM:602225: Cone-rod retinal dystrophy-2
OMIM:120970: Leber congenital amaurosis due to defect in CRX
OMIM:204000: Retinitis pigmentosa, late-onset dominant
LIM homeobox transcription factor 1-beta (O60663) (SMART) OMIM:602575: Nail-patella syndrome
OMIM:161200: Nail-patella syndrome with open-angle glaucoma
Homeobox protein TGIF1 (Q15583) (SMART) OMIM:142946: Holoprosencephaly-4
Pancreas/duodenum homeobox protein 1 (P52945) (SMART) OMIM:600733: Pancreatic agenesis
OMIM:260370: MODY, type IV
Pituitary homeobox 2 (Q99697) (SMART) OMIM:137600: Iridogoniodysgenesis syndrome
OMIM:601542: Rieger syndrome
OMIM:180500: Iridogoniodysgenesis syndrome-2
POU domain, class 3, transcription factor 4 (P49335) (SMART) OMIM:300039: Deafness, X-linked 3, conductive, with stapes fixation
Paired box protein Pax-3 (P23760) (SMART) OMIM:193500: Waardenburg syndrome, type I ; Waardenburg syndrome, type III
OMIM:148820: Rhabdomyosarcoma, alveolar
OMIM:268220: Craniofacial-deafness-hand syndrome
- Metabolism (metabolic pathways involving proteins which contain this domain)
% proteins involved KEGG pathway ID Description 73.47 map04950 Maturity onset diabetes of the young 8.16 map04930 Type II diabetes mellitus 8.16 map04350 TGF-beta signaling pathway 7.14 map05215 Prostate cancer 3.06 map04111 Cell cycle - yeast
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with HOX domain which could be assigned to a KEGG orthologous group, and not all proteins containing HOX domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
- Structure (3D structures containing this domain)
3D Structures of HOX domains in PDB
PDB code Main view Title 1ahd Determination of the nmr solution structure of an antennapedia homeodomain-dna complex 1akh Mat a1/alpha2/dna ternary complex 1apl Crystal structure of a mat-alpha2 homeodomain-operator complex suggests a general model for homeodomain-dna interactions 1au7 Pit-1 mutant/dna complex 1b72 Pbx1, homeobox protein hox-b1/dna ternary complex 1b8i Structure of the homeotic ubx/exd/dna ternary complex 1bw5 The nmr solution structure of the homeodomain of the rat insulin gene enhancer protein isl-1, 50 structures 1cqt Crystal structure of a ternary complex containing an oca-b peptide, the oct-1 pou domain, and an octamer element 1du0 Engrailed homeodomain q50a variant dna complex 1du6 Solution structure of the truncated pbx homeodomain 1e3o Crystal structure of oct-1 pou dimer bound to more 1enh Structural studies of the engrailed homeodomain 1f43 Solution structure of the mata1 homeodomain 1fjl Homeodomain from the drosophila paired protein bound to a dna oligonucleotide 1ftt Thyroid transcription factor 1 homeodomain (rattus norvegicus) 1ftz Nuclear magnetic resonance solution structure of the fushi tarazu homeodomain from drosophila and comparison with the antennapedia homeodomain 1gt0 Crystal structure of a pou/hmg/dna ternary complex 1hdd Crystal structure of an engrailed homeodomain-dna complex at 2.8 angstroms resolution: a framework for understanding homeodomain-dna interactions 1hdp Solution structure of a pou-specific homeodomain: 3d-nmr studies of human b-cell transcription factor oct-2 1hf0 Crystal structure of the dna-binding domain of oct-1 bound to dna as a dimer 1hom Determination of the three-dimensional structure of the antennapedia homeodomain from drosophila in solution by 1h nuclear magnetic resonance spectroscopy 1ic8 Hepatocyte nuclear factor 1a bound to dna : mody3 gene product 1ig7 Msx-1 homeodomain/dna complex structure 1jgg Even-skipped homeodomain complexed to at-rich dna 1k61 Matalpha2 homeodomain bound to dna 1le8 Crystal structure of the mata1/matalpha2-3a heterodimer bound to dna complex 1lfb The x-ray structure of an atypical homeodomain present in the rat liver transcription factor lfb1(slash)hnf1 and implications for dna binding 1lfu Nmr solution stucture of the extended pbx homeodomain bound to dna 1mh3 Maltose binding-a1 homeodomain protein chimera, crystal form i 1mh4 Maltose binding-a1 homeodomain protein chimera, crystal form ii 1mnm Yeast matalpha2/mcm1/dna ternary transcription complex crystal structure 1nk2 Vnd/nk-2 homeodomain/dna complex, nmr, 20 structures 1nk3 Vnd/nk-2 homeodomain/dna complex, nmr, minimized average structure 1o4x Ternary complex of the dna binding domains of the oct1 and sox2 transcription factors with a 19mer oligonucleotide from the hoxb1 regulatory element 1ocp Solution structure of oct3 pou-homeodomain 1oct Crystal structure of the oct-1 pou domain bound to an octamer site: dna recognition with tethered dna-binding modules 1p7i Crystal structure of engrailed homeodomain mutant k52a 1p7j Crystal structure of engrailed homeodomain mutant k52e 1pog Solution structure of the oct-1 pou-homeo domain determined by nmr and restrained molecular dynamics 1puf Crystal structure of hoxa9 and pbx1 homeodomains bound to dna 1qry Homeobox protein vnd (ventral nervous system defective protein) 1s7e Solution structure of hnf-6 1san The des(1-6)antennapedia homeodomain: comparison of the nmr solution structure and the dna binding affinity with the intact antennapedia homeodomain 1uhs Solution structure of mouse homeodomain-only protein hop 1vnd Vnd/nk-2 protein (homeodomain), nmr 1wi3 Solution structure of the homeodomain of kiaa1034 protein 1x2m Solution structure of the homeobox domain of mouse lag1 longevity assurance homolog 6 1x2n Solution structure of the homeobox domain of human homeobox protein pknox1 1yrn Crystal structure of the mata1/matalpha2 homeodomain heterodimer bound to dna 1yz8 Solution structure of the k50 class homeodomain pitx2 bound to dna and implications for mutations that cause rieger syndrome 1zq3 Nmr solution structure of the bicoid homeodomain bound to the consensus dna binding site taatcc 1ztr Solution structure of engrailed homeodomain l16a mutant 2cqx Solution structure of rsgi ruh-034, a homeodomain from mouse cdna 2cra Solution structure of the homeobox domain of human homeo box b13 2cue Solution structure of the homeobox domain of the human paired box protein pax-6 2cuf Solution structure of the homeobox domain of the human hypothetical protein flj21616 2d5v Crystal structure of hnf-6alpha dna-binding domain in complex with the ttr promoter 2da1 Solution structure of the first homeobox domain of at- binding transcription factor 1 (atbf1) 2da2 Solution structure of the second homeobox domain of at- binding transcription factor 1 (atbf1) 2da3 Solution structure of the third homeobox domain of at- binding transcription factor 1 (atbf1) 2da4 Solution structure of the homeobox domain of the hypothetical protein, dkfzp686k21156 2da5 Solution structure of the second homeobox domain of zinc fingers and homeoboxes protein 3 (triple homeobox 1 protein) 2da6 Solution structure of the homeobox domain of hepatocyte nuclear factor 1-beta (hnf-1beta) 2da7 Solution structure of the homeobox domain of zinc finger homeobox protein 1b (smad interacting protein 1) 2djn The solution structure of the homeobox domain of human homeobox protein dlx-5 2dmn The solution structure of the homeobox domain of human homeobox protein tgif2lx 2dmp Solution structure of the third homeobox domain of zinc fingers and homeoboxes protein 2 2dmq Solution structure of the homeobox domain of lim/homeobox protein lhx9 2dms Solution structure of the homeobox domain of homeobox protein otx2 2dmt Solution structure of the homeobox domain of homeobox protein barh-like 1 2dmu Solution structure of the homeobox domain of homeobox protein goosecoid 2dn0 Solution structure of the second homeobox domain of human zinc fingers and homeoboxes protein 3 2e19 Solution structure of the homeobox domain from human nil-2- a zinc finger protein, transcription factor 8 2e1o Solution structure of rsgi ruh-028, a homeobox domain from human cdna 2ecb The solution structure of the third homeobox domain of human zinc fingers and homeoboxes protein 2ecc Solution structure of the second homeobox domain of human homeodomain leucine zipper-encoding gene (homez) 2h1k Crystal structure of the pdx1 homeodomain in complex with dna 2h8r Hepatocyte nuclear factor 1b bound to dna: mody5 gene product 2hdd Engrailed homeodomain q50k variant dna complex 2hi3 Solution structure of the homeodomain-only protein hop 2hoa Structure determination of the antp(c39->s) homeodomain from nuclear magnetic resonance data in solution using a novel strategy for the structure calculation with the programs diana, caliba, habas and glomsa 2hos Phage-selected homeodomain bound to unmodified dna 2hot Phage selected homeodomain bound to modified dna 2jwt Solution structure of engrailed homeodomain wt 2k40 Nmr structure of hesx-1 homeodomain double mutant r31l/e42l 2lfb Homeodomain from rat liver lfb1/hnf1 transcription factor, nmr, 20 structures 2p81 Engrailed homeodomain helix-turn-helix motif 2r5y Structure of scr/exd complex bound to a consensus hox-exd site 2r5z Structure of scr/exd complex bound to a dna sequence derived from the fkh gene 2vi6 Crystal structure of the nanog homeodomain 3cmy Structure of a homeodomain in complex with dna 3d1n Structure of human brn-5 transcription factor in complex with corticotrophin-releasing hormone gene promoter 3hdd Engrailed homeodomain dna complex 9ant Antennapedia homeodomain-dna complex
- Links (links to other resources describing this domain)
PFAM homeobox INTERPRO IPR001356 PROSITE HOMEOBOX_2