Homeodomain fold
Encyclopedia
The homeodomain fold is a protein
structural domain that binds DNA
or RNA
and is thus commonly found in transcription factor
s. The fold consists of a 60-amino acid
helix-turn-helix
structure in which three alpha helices
are connected by short loop regions. The N-terminal two helices are antiparallel
and the longer C-terminal helix is roughly perpendicular to the axes established by the first two. It is this third helix that interacts directly with DNA. Homeodomain folds are found exclusively in eukaryote
s but have high homology to lambda phage
proteins that alter the expression of genes in prokaryote
s. Many homeodomains induce cellular differentiation
by initiating the cascades of coregulated genes required to produce individual tissues
and organ
s, while homeodomain proteins like Nanog
are involved in maintaining pluripotency.
s and invertebrate
s. The existence of homeoboxes was first discovered in Drosophila
, where the radical alterations that resulted from mutations in homeobox genes were termed homeotic mutations. The most famous such mutation is Antennapedia
, in which legs grow from the head of a fly instead of the expected antennae. Homeobox genes are critical in the establishment of body axes during embryogenesis
.
The consensus 60-polypeptide chain is http://www.csb.ki.se/groups/tbu/homeo/consensus.gif(typical intron position noted with dashes)
RRRKRTA-YTRYQLLE-LEKEFLF-NRYLTRRRRIELAHSL-NLTERHIKIWFQN-RRMK-WKKEN
The motif is highly conserved over hundreds of millions of years of evolutionary history, with typically 80% match in the corresponding nucleotide sequence to the consensus sequence across species, genera and phyla.
and lysine
residues, which form hydrogen bond
s to the DNA backbone; conserved hydrophobic residues in the center of the recognition helix aid in stabilizing the helix packing. Homeodomain proteins show a preference for the DNA sequence 5'-ATTA-3'; sequence-independent binding occurs with significantly lower affinity.
motifs and also binds DNA. The two domains are linked by a flexible loop that is long enough to stretch around the DNA helix, allowing the two domains to bind on opposite sides of the target DNA, collectively covering an eight-base segment with consensus sequence
5'-ATGCAAAT-3'. The individual domains of POU proteins bind DNA only weakly, but have strong sequence-specific affinity when linked. Interestingly, the POU domain itself has significant structural similarity with repressors expressed in bacteriophage
s, particularly lambda phage
.
/Dlx2
, Dlx3
/Dlx4
and Dlx5
/Dlx6
. All six are homologs of the fly gene Distal-less. Dlx genes are involved in the development of the nervous system and of limbs.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
structural domain that binds DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
or RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
and is thus commonly found in transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. The fold consists of a 60-amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
helix-turn-helix
Helix-turn-helix
In proteins, the helix-turn-helix is a major structural motif capable of binding DNA. It is composed of two α helices joined by a short strand of amino acids and is found in many proteins that regulate gene expression...
structure in which three alpha helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
are connected by short loop regions. The N-terminal two helices are antiparallel
Antiparallel (biochemistry)
In biochemistry, two molecules are antiparallel if they run side-by-side in opposite directions or when both strands are complimentary to each other....
and the longer C-terminal helix is roughly perpendicular to the axes established by the first two. It is this third helix that interacts directly with DNA. Homeodomain folds are found exclusively in eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s but have high homology to lambda phage
Lambda phage
Enterobacteria phage λ is a temperate bacteriophage that infects Escherichia coli.Lambda phage is a virus particle consisting of a head, containing double-stranded linear DNA as its genetic material, and a tail that can have tail fibers. The phage particle recognizes and binds to its host, E...
proteins that alter the expression of genes in prokaryote
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...
s. Many homeodomains induce cellular differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
by initiating the cascades of coregulated genes required to produce individual tissues
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
and organ
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
s, while homeodomain proteins like Nanog
NANOG
The North American Network Operators' Group is an educational and operational forum for the coordination and dissemination of technical information related to backbone/enterprise networking technologies and operational practices. It runs meetings, talks, surveys, and an influential mailing list...
are involved in maintaining pluripotency.
Homeobox genes
The homeobox is a stretch of DNA about 180 nucleotides long that encodes a homeodomain. Homeobox genes code for homeodomain proteins in both vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s and invertebrate
Invertebrate
An invertebrate is an animal without a backbone. The group includes 97% of all animal species – all animals except those in the chordate subphylum Vertebrata .Invertebrates form a paraphyletic group...
s. The existence of homeoboxes was first discovered in Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
, where the radical alterations that resulted from mutations in homeobox genes were termed homeotic mutations. The most famous such mutation is Antennapedia
Antennapedia
Antennapedia is a HOM-C gene first discovered in Drosophila which controls the formation of legs during development. Loss-of-function mutations in the regulatory region of this gene result in the development of the second leg pair into ectopic antennae...
, in which legs grow from the head of a fly instead of the expected antennae. Homeobox genes are critical in the establishment of body axes during embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
.
The consensus 60-polypeptide chain is http://www.csb.ki.se/groups/tbu/homeo/consensus.gif(typical intron position noted with dashes)
RRRKRTA-YTRYQLLE-LEKEFLF-NRYLTRRRRIELAHSL-NLTERHIKIWFQN-RRMK-WKKEN
The motif is highly conserved over hundreds of millions of years of evolutionary history, with typically 80% match in the corresponding nucleotide sequence to the consensus sequence across species, genera and phyla.
Sequence specificity
Homeodomains can bind both specifically and nonspecifically to B-DNA with the C-terminal recognition helix aligning in the DNA's major groove and the unstructured peptide "tail" at the N-terminus aligning in the minor groove. The recognition helix and the inter-helix loops are rich in arginineArginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
and lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residues, which form hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
s to the DNA backbone; conserved hydrophobic residues in the center of the recognition helix aid in stabilizing the helix packing. Homeodomain proteins show a preference for the DNA sequence 5'-ATTA-3'; sequence-independent binding occurs with significantly lower affinity.
POU proteins
Proteins containing a POU region consist of a homeodomain and a separate, structurally homologous POU domain that contains two helix-turn-helixHelix-turn-helix
In proteins, the helix-turn-helix is a major structural motif capable of binding DNA. It is composed of two α helices joined by a short strand of amino acids and is found in many proteins that regulate gene expression...
motifs and also binds DNA. The two domains are linked by a flexible loop that is long enough to stretch around the DNA helix, allowing the two domains to bind on opposite sides of the target DNA, collectively covering an eight-base segment with consensus sequence
Consensus sequence
In molecular biology and bioinformatics, consensus sequence refers to the most common nucleotide or amino acid at a particular position after multiple sequences are aligned. A consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are...
5'-ATGCAAAT-3'. The individual domains of POU proteins bind DNA only weakly, but have strong sequence-specific affinity when linked. Interestingly, the POU domain itself has significant structural similarity with repressors expressed in bacteriophage
Bacteriophage
A bacteriophage is any one of a number of viruses that infect bacteria. They do this by injecting genetic material, which they carry enclosed in an outer protein capsid...
s, particularly lambda phage
Lambda phage
Enterobacteria phage λ is a temperate bacteriophage that infects Escherichia coli.Lambda phage is a virus particle consisting of a head, containing double-stranded linear DNA as its genetic material, and a tail that can have tail fibers. The phage particle recognizes and binds to its host, E...
.
Dlx proteins
Vertebrates have six genes from the Dlx family of homeodomain transcription factors, arranged into three clusters: Dlx1DLX1
Homeobox protein DLX-1 is a protein that in humans is encoded by the DLX1 gene.- Function :This gene encodes a member of a homeobox transcription factor gene family similar to the Drosophila distal-less gene. The encoded protein is localized to the nucleus where it may function as a transcriptional...
/Dlx2
DLX2
Homeobox protein DLX-2 is a protein that in humans is encoded by the DLX2 gene.-Interactions:DLX2 has been shown to interact with DLX5, MSX1 and Msh homeobox 2.-Further reading:...
, Dlx3
DLX3 (gene)
Homeobox protein DLX-3 is a protein that in humans is encoded by the DLX3 gene....
/Dlx4
DLX4
Homeobox protein DLX-4 is a protein that in humans is encoded by the DLX4 gene.- External links :...
and Dlx5
DLX5
Homeobox protein DLX-5 is a protein that in humans is encoded by the DLX5 gene.- Function :This gene encodes a member of a homeobox transcription factor gene family similar to the Drosophila distal-less gene. The encoded protein may play a role in bone development and fracture healing...
/Dlx6
DLX6
Homeobox protein DLX-6 is a protein that in humans is encoded by the DLX6 gene.-Further reading:...
. All six are homologs of the fly gene Distal-less. Dlx genes are involved in the development of the nervous system and of limbs.
Further reading
- Branden C, Tooze J. (1999). Introduction to Protein Structure 2nd ed. Garland Publishing: New York, NY. (See especially pp159–66.)