PHD finger
Encyclopedia
The PHD finger was discovered in 1993 as a Cys4-His-Cys3 motif in the homeodomain protein
HAT3 in Arabidopsis thaliana.
The PHD finger motif resembles the metal binding RING domain (Cys3-His-Cys4) and FYVE domain
. It occurs as a single finger, but often in clusters of two or three, and it also occurs together with other domains, such as the chromodomain
and the bromodomain
.
-mediated gene regulation
. The PHD finger occurs in proteins such as the transcriptional co-activators p300
and CBP
, Polycomb
-like protein (Pcl), Trithorax-group proteins
like ASH1L
, ASH2L
and MLL
, the autoimmune regulator
(AIRE), Mi-2 complex (part of histone deacetylase complex), the co-repressor TIF1, the newly discovered JARID1-family of demethylases and many more.
(Williams Syndrome
Transcription Factor) shows that the conserved cysteine
s and histidine
coordinate two Zn2+ ions. In general, the PHD finger adopts a globular fold, consisting of a two-stranded beta-sheet and an alpha-helix. The region consisting of these secondary structure
s and the residues involved in coordinating the zinc
-ions are very conserved among species. The loop regions I and II are variable and could contribute functional specificity to the different PHD fingers.
, YNG1 and NURF, have been reported to bind to histone
H3 tri-methylated
on lysine
4 (H3K4me3), while other PHD fingers have tested negative in such assays. Interestingly, a protein called SMCX (or JARID1C
) has a PHD finger, which has been reported to bind histone H3 tri-methylated lysine 9 (H3K9me3). Based on these recent publications, binding to tri-methylated lysines on histones may therefore be a property widespread among PHD fingers. Domains that bind to modified histones, are called epigenetic readers as they specifically recognize the modified version of the residue and binds to it.
The modification H3K4me3 is associated with the transcription start site of active genes, while H3K9me3 is associated with inactive genes. The modifications of the histone lysines are dynamic, as there are methylase
s that add methyl groups to the lysines, and there are demethylase
s that remove methyl groups. The SMCX protein is actually a histone H3 lysine 4 demethylase, which means it is an enzyme that can remove the methyl groups of lysine 4 on histone 3 (making it H3K4me2 or H3K4me1). One can only speculate if the H3K9me3-binding of SMCX PHD domain provides a crosstalk between trimethylation of H3K9 and the demethylation of H3K4me3. Such crosstalks have been suggested earlier with other domains involved in chromatin regulation, and may provide a strictly coordinated regulation.
Another example is the PHD finger of the BHC80/PHF21A
protein, which is a component of the LSD1
complex. In this complex, LSD1 specifically demethylates H3K4me2 to H3K4me0, and BHC80 binds H3K4me0 through its PHD finger to stabilize the complex at its target promoters, presumably to prevent further re-methylation. This is the first example of a PHD finger recognizing lysine methyl-zero status.
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...
HAT3 in Arabidopsis thaliana.
The PHD finger motif resembles the metal binding RING domain (Cys3-His-Cys4) and FYVE domain
FYVE domain
FYVE zinc finger domain is named after the four cysteine-rich proteins: Fab 1 , YOTB, Vac 1 , and EEA1, in which it has been found....
. It occurs as a single finger, but often in clusters of two or three, and it also occurs together with other domains, such as the chromodomain
Chromodomain
A chromodomain is a protein structural domain of about 40-50 amino acid residues commonly found in proteins associated with the remodeling and manipulation of chromatin. The domain is highly conserved among both plants and animals, and is represented in a large number of different proteins in many...
and the bromodomain
Bromodomain
A bromodomain is a protein domain that recognizes acetylated lysine residues such as those on the N-terminal tails of histones. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha...
.
PHD finger in proteins related to epigenetics
The PHD finger, approximately 50-80 aminoacids in length, is found in more than 100 human proteins. Several of the proteins it occurs in are found in the nucleus, and are involved in chromatinChromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
-mediated gene regulation
Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
. The PHD finger occurs in proteins such as the transcriptional co-activators p300
EP300
E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...
and CBP
CREB binding protein
CREB-binding protein, also known as CREBBP or CBP, is a protein that in humans is encoded by the CREBBP gene.The CREB protein carries out its function by activating transcription, where interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor...
, Polycomb
Polycomb-group proteins
Polycomb-group proteins are a family of proteins first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place...
-like protein (Pcl), Trithorax-group proteins
Trithorax-group proteins
Trithorax-group proteins are chromatin regulatory proteins which generally act to maintain gene expression. This group of proteins is rather heterogeneous and contains members that form several multiprotein chromatin complexes...
like ASH1L
ASH1L
Probable histone-lysine N-methyltransferase ASH1L is an enzyme that in humans is encoded by the ASH1L gene.-Further reading:...
, ASH2L
ASH2L
Set1/Ash2 histone methyltransferase complex subunit ASH2 is an enzyme that in humans is encoded by the ASH2L gene.-Interactions:ASH2L has been shown to interact with MLL.-Further reading:...
and MLL
MLL (gene)
Histone-lysine N-methyltransferase HRX is an enzyme that in humans is encoded by the MLL gene.MLL is a histone methyltransferase deemed a positive global regulator of gene transcription...
, the autoimmune regulator
Autoimmune regulator
The autoimmune regulator is a protein that in humans is encoded by the AIRE gene. AIRE is a transcription factor expressed in the medulla of the thymus and controls the mechanism that prevents the immune system from attacking the body itself....
(AIRE), Mi-2 complex (part of histone deacetylase complex), the co-repressor TIF1, the newly discovered JARID1-family of demethylases and many more.
Structure data on the PHD finger
The NMR structure of the PHD finger from human WSTFBAZ1B
Tyrosine-protein kinase BAZ1B is an enzyme that in humans is encoded by the BAZ1B gene.-Animal models:Model organisms have been used in the study of BAZ1B function...
(Williams Syndrome
Williams syndrome
Williams syndrome is a rare neurodevelopmental disorder characterized by a distinctive, "elfin" facial appearance, along with a low nasal bridge; an unusually cheerful demeanor and ease with strangers; developmental delay coupled with strong language skills; and cardiovascular problems, such as...
Transcription Factor) shows that the conserved cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
s and histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
coordinate two Zn2+ ions. In general, the PHD finger adopts a globular fold, consisting of a two-stranded beta-sheet and an alpha-helix. The region consisting of these secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
s and the residues involved in coordinating the zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
-ions are very conserved among species. The loop regions I and II are variable and could contribute functional specificity to the different PHD fingers.
Function of the PHD finger
Recently the PHD fingers of some proteins, including ING2ING2
Inhibitor of growth protein 2 is a protein that in humans is encoded by the ING2 gene.-Further reading:...
, YNG1 and NURF, have been reported to bind to histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
H3 tri-methylated
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
on 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....
4 (H3K4me3), while other PHD fingers have tested negative in such assays. Interestingly, a protein called SMCX (or JARID1C
JARID1C
Lysine-specific demethylase 5C is an enzyme that in humans is encoded by the KDM5C gene....
) has a PHD finger, which has been reported to bind histone H3 tri-methylated lysine 9 (H3K9me3). Based on these recent publications, binding to tri-methylated lysines on histones may therefore be a property widespread among PHD fingers. Domains that bind to modified histones, are called epigenetic readers as they specifically recognize the modified version of the residue and binds to it.
The modification H3K4me3 is associated with the transcription start site of active genes, while H3K9me3 is associated with inactive genes. The modifications of the histone lysines are dynamic, as there are methylase
Methylase
A methylase is an enzyme that attaches a methyl group to a molecule.These are found in prokaryotes and eukaryotes. Bacteria use methylase to differentiate between foreign genetic material and their own, thus protecting their DNA from their own immune system...
s that add methyl groups to the lysines, and there are demethylase
Demethylase
Demethylases are enzymes that remove methyl groups from proteins and other substances. They are used in a variety of processes, such as in chemotaxis signal transduction.-Hydrolytic demethylation:A good example of a demethylase is the activated Demethylases are enzymes that remove methyl (CH3-)...
s that remove methyl groups. The SMCX protein is actually a histone H3 lysine 4 demethylase, which means it is an enzyme that can remove the methyl groups of lysine 4 on histone 3 (making it H3K4me2 or H3K4me1). One can only speculate if the H3K9me3-binding of SMCX PHD domain provides a crosstalk between trimethylation of H3K9 and the demethylation of H3K4me3. Such crosstalks have been suggested earlier with other domains involved in chromatin regulation, and may provide a strictly coordinated regulation.
Another example is the PHD finger of the BHC80/PHF21A
PHF21A
PHD finger protein 21A is a protein that in humans is encoded by the PHF21A gene.-Interactions:PHF21A has been shown to interact with HMG20B, HDAC1, Histone deacetylase 2 and RCOR1....
protein, which is a component of the LSD1
LSD1
LSD1 is a gene which codes a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysines 4 and 9 .-See also:* Histone methylation...
complex. In this complex, LSD1 specifically demethylates H3K4me2 to H3K4me0, and BHC80 binds H3K4me0 through its PHD finger to stabilize the complex at its target promoters, presumably to prevent further re-methylation. This is the first example of a PHD finger recognizing lysine methyl-zero status.