Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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HOX Homeodomain

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)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 14886 HOX domains in 13991 proteins in SMART's nrdb database.

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.

  Useful shortcuts: Expand all nodes or Collapse tree
  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 OMIM:182230:
  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: 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 OMIM:603714: Holoprosencephaly-2 OMIM:157170:
  Homeobox protein Nkx-2.5 (P52952) (SMART)	OMIM:600584: Atrial septal defect with atrioventricular conduction defects OMIM:108900:
  Homeobox protein MSX-1 (P28360) (SMART)	OMIM:142983: Hypodontia, autosomal dominant OMIM:106600: Hypodontia with orofacial cleft OMIM:106600:
  Homeobox protein aristaless-like 4 (Q9H161) (SMART)	OMIM:168500: Parietal foramina OMIM:605420: Parietal foramina 2 OMIM:168500:
  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 OMIM:137750:
  Homeobox protein TGIF1 (Q15583) (SMART)	OMIM:142946: Holoprosencephaly-4 OMIM:602630: Holoprosencephaly-4 OMIM:142946:
  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 OMIM:137600:
  POU domain, class 3, transcription factor 4 (P49335) (SMART)	OMIM:300039: Deafness, X-linked 3, conductive, with stapes fixation OMIM:304400:
  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 OMIM:122880:

• 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

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