DHHC domain
Encyclopedia
In molecular biology the DHHC domain is a protein domain
that acts as an enzyme
, which adds a palmitoyl
chemical group to protein
s in order to anchor them to cell membrane
s. The DHHC domain was discovered in 1999 and named after a conserved sequence motif
found in its protein sequence. Roth and colleagues showed that the yeast
Akr1p protein could palmitoylate
Yck2p in vitro
and inferred that the DHHC domain defined a large family of palmitoyltransferases. In mammals twenty three members of this family have been identified and their substrate specificities investigated. Some members of the family such as ZDHHC3
and ZDHHC7 enhance palmitoylation of proteins such as PSD-95
, SNAP-25
, GAP43
, Gαs. Others such as ZDHHC9
showed specificity only toward the H-Ras
protein. However, a recent study questions the involvement of classical enzyme-substrate recognition and specificity in the palmitoylation reaction. Several members of the family have been implicated in human diseases.
residues for function. In the DHHC domain there is a tetrapeptide motif composed of aspartate-histidine
-histidine-cysteine
. However this short sequence is embedded in a larger region of about fifty amino acids in length that shares many more conserved amino acids. The canonical DHHC domain can be described with the following sequence motif:
C-x2-C-x9-HC-x2-C-x4-DHHC-x5-C-x4-N-x3-F (x shows region of unconserved residues)
However many examples of DHHC domains are known that do not contain all these conserved residues. In addition to the central DHHC domain three further sequence motifs have been identified in members of the DHHC family. A DPG (aspartate-proline
-glycine
) motif has been identified just to the C-terminus of the second transmembrane region. A TTxE (threonine
-threonine-any-glutamate) motif has also been identified after the fourth transmembrane helix. A third motif towards the C-terminus of many proteins has been identified that contains a conserved aromatic amino acid, a glycine and an asparagine
.
Further studies in 2009 showed that of the 5 classes studied, 2-(2-hydroxy-5-nitro-benzylidene)-benzo[b]thiophen-3-one was shown to behave similarly to 2-Bromopalmitate and were identified as able to inhibit
the palmitoylation reaction of a range of DHHC domain containing proteins. Inhibition with 2-Bromopalmitate was found to be irreversible, the other however was found to be mostly reversible. Because of the roles of DHHC domain proteins in human diseases it has been suggested that chemical inhibitors of specific DHHC proteins may be a potential route to treatment of disease.
s within the DHHC domain of ZDHHC9
were identified in X-linked mental retardation
associated
with a Marfanoid Habitus
. A potential link of ZDHHC11 with bladder cancer has been suggested by the discovery that 5 out of 9 high-grade bladder cancer samples surveyed contained a duplication of the 5p15.33 genomic region. However, this region contains another gene TPPP
which may be the causative gene. The HIP14
palmitoyltransferase is responsible for palmitoylating the Huntingtin
protein. Expansions of the triplet repeat in the huntington's gene leads to loss of interaction with HIP14 which Yanai and colleagues speculate is involved in the pathology of Huntington's disease
. A gene knockout experiment of the mouse homologue of ZDHHC13 showed hair loss, severe osteoporosis
, and systemic amyloidosis
, both of AL and AA
depositions.
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
that acts as an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, which adds a palmitoyl
Palmitic acid
Palmitic acid, or hexadecanoic acid in IUPAC nomenclature, is one of the most common saturated fatty acids found in animals and plants. Its molecular formula is CH314CO2H. As its name indicates, it is a major component of the oil from palm trees . Palmitate is a term for the salts and esters of...
chemical group to protein
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...
s in order to anchor them to cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s. The DHHC domain was discovered in 1999 and named after a conserved sequence motif
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
found in its protein sequence. Roth and colleagues showed that the yeast
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
Akr1p protein could palmitoylate
Palmitoylation
S-Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their...
Yck2p in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and inferred that the DHHC domain defined a large family of palmitoyltransferases. In mammals twenty three members of this family have been identified and their substrate specificities investigated. Some members of the family such as ZDHHC3
ZDHHC3
Palmitoyltransferase ZDHHC3 is an enzyme that in humans is encoded by the ZDHHC3 gene that contains a DHHC domain.-Further reading:...
and ZDHHC7 enhance palmitoylation of proteins such as PSD-95
DLG4
PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene....
, SNAP-25
SNAP-25
Synaptosomal-associated protein 25 is a protein that in humans is encoded by the SNAP25 gene. The SNAP-25 protein is a component of the SNARE complex, which is proposed to account for the specificity of membrane fusion and to directly execute fusion by forming a tight complex that brings the...
, GAP43
Gap-43 protein
Growth Associated Protein 43 also known as Gap43 is a protein that in humans is encoded by the GAP43 gene.Gap43 has been termed a 'growth' or 'plasticity' protein because it is expressed at high levels in neuronal growth cones during development, during axonal regeneration and is phosphorylated...
, Gαs. Others such as ZDHHC9
ZDHHC9
Palmitoyltransferase ZDHHC9 is an enzyme that in humans is encoded by the ZDHHC9 gene that contains a DHHC domain.-Further reading:...
showed specificity only toward the H-Ras
HRAS
GTPase HRas also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. The HRAS gene is located on the short arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549.- Function :...
protein. However, a recent study questions the involvement of classical enzyme-substrate recognition and specificity in the palmitoylation reaction. Several members of the family have been implicated in human diseases.
Sequence motifs
Conserved motifs within protein sequences point towards the most important amino acidAmino 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...
residues for function. In the DHHC domain there is a tetrapeptide motif composed of aspartate-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...
-histidine-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...
. However this short sequence is embedded in a larger region of about fifty amino acids in length that shares many more conserved amino acids. The canonical DHHC domain can be described with the following sequence motif:
However many examples of DHHC domains are known that do not contain all these conserved residues. In addition to the central DHHC domain three further sequence motifs have been identified in members of the DHHC family. A DPG (aspartate-proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
) motif has been identified just to the C-terminus of the second transmembrane region. A TTxE (threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
-threonine-any-glutamate) motif has also been identified after the fourth transmembrane helix. A third motif towards the C-terminus of many proteins has been identified that contains a conserved aromatic amino acid, a glycine and an asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
.
Chemical inhibitors
In 2006, five chemical classes of small molecules were discovered which were shown to act against palmitoyltransferases.Further studies in 2009 showed that of the 5 classes studied, 2-(2-hydroxy-5-nitro-benzylidene)-benzo[b]thiophen-3-one was shown to behave similarly to 2-Bromopalmitate and were identified as able to inhibit
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
the palmitoylation reaction of a range of DHHC domain containing proteins. Inhibition with 2-Bromopalmitate was found to be irreversible, the other however was found to be mostly reversible. Because of the roles of DHHC domain proteins in human diseases it has been suggested that chemical inhibitors of specific DHHC proteins may be a potential route to treatment of disease.
In human disease
Several proteins containing DHHC domains have been implicated in human disease. Two missense mutationMissense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
s within the DHHC domain of ZDHHC9
ZDHHC9
Palmitoyltransferase ZDHHC9 is an enzyme that in humans is encoded by the ZDHHC9 gene that contains a DHHC domain.-Further reading:...
were identified in X-linked mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
associated
with a Marfanoid Habitus
Marfan syndrome
Marfan syndrome is a genetic disorder of the connective tissue. People with Marfan's tend to be unusually tall, with long limbs and long, thin fingers....
. A potential link of ZDHHC11 with bladder cancer has been suggested by the discovery that 5 out of 9 high-grade bladder cancer samples surveyed contained a duplication of the 5p15.33 genomic region. However, this region contains another gene TPPP
TPPP
Tubulin polymerization-promoting protein is a protein that in humans is encoded by the TPPP gene.This protein has been linked to multiple sclerosis myelin lesions and CSF abnormalities in multiple sclerosis patients....
which may be the causative gene. The HIP14
ZDHHC17
Palmitoyltransferase ZDHHC17 is an enzyme that contains a DHHC domain that in humans is encoded by the ZDHHC17 gene.-Interactions:ZDHHC17 has been shown to interact with Huntingtin.-Further reading:...
palmitoyltransferase is responsible for palmitoylating the Huntingtin
Huntingtin
The Huntingtin gene, also called HTT or HD gene, is the IT15 gene which codes for a protein called the huntingtin protein...
protein. Expansions of the triplet repeat in the huntington's gene leads to loss of interaction with HIP14 which Yanai and colleagues speculate is involved in the pathology of Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
. A gene knockout experiment of the mouse homologue of ZDHHC13 showed hair loss, severe osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, and systemic amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
, both of AL and AA
AA amyloidosis
AA amyloidosis is a form of amyloidosis associated with serum amyloid A protein , an acute-phase protein. It causes reactive systemic amyloidosis, as a "reaction" to inflammation, but also familial Mediterranean fever, which is an inheritable condition.-Presentation:The common feature to conditions...
depositions.