In molecular biology the DHHC domain is a
protein domain
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...
that acts as an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
, which adds a
palmitoyl chemical group to
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s in order to anchor them to
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s. The DHHC domain was discovered in 1999 and named after a conserved
sequence motif
In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an ''N''-glycosylation site motif can be defined as ''As ...
found in its
protein sequence
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesi ...
.
Roth and colleagues showed that the
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
Akr1p protein could
palmitoylate Yck2p ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' 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
PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene.
PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
,
SNAP-25
Synaptosomal-Associated Protein, 25kDa (SNAP-25) is a Target Soluble NSF (''N''-ethylmaleimide-sensitive factor) Attachment Protein Receptor ( t-SNARE) protein encoded by the ''SNAP25'' gene found on chromosome 20p12.2 in humans. SNAP-25 is a com ...
,
GAP43,
Gαs
The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein.
Gsα is the founding m ...
. Others such as
ZDHHC9 showed specificity only toward the
H-Ras
GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 t ...
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 acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
residues for function. In the DHHC domain there is a tetrapeptide motif composed of
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
-
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
-histidine-
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
. 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 (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
-
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
) motif has been identified just to the
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
of the second
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
region.
A ''TTxE'' (
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
-threonine-any-
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
) 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 (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
called the PaCCT motif (PAlmitoiltransferase Conserved C-Terminus motif).
Structure and mechanism
Several structures of the DHHC domain has been solved, and it is known to run on a linearly-arranged
catalytic triad
A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, acylases, lip ...
of Asp153, His154, and Cys156. It runs on a
ping-pong mechanism
Enzyme kinetics is the study of the rates of enzyme-catalysed chemical reactions. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction are investigated. Studying an enzyme's kinetics in t ...
, where the cysteine attacks the acyl-CoA to form an S-acylated DHHC, and then the acyl group is transferred to the substrate. DHHR enzymes exist, and they (as well as some DHHC enzymes) may use a
ternary complex
A ternary complex is a protein complex containing three different molecules that are bound together. In structural biology, ''ternary complex'' can also be used to describe a crystal containing a protein with two small molecules bound, for example ...
mechanism instead.
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
hiophen-3-one was shown to behave similarly to
2-Bromopalmitate and were identified as able to
inhibit
Inhibitor or inhibition may refer to:
In biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotr ...
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 mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
s within the DHHC domain of
ZDHHC9 were identified in
X-linked
Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...
mental retardation
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signific ...
associated
with a
Marfanoid Habitus
Marfanoid (or Marfanoid habitus) is a constellation of Symptom, symptoms resembling those of Marfan syndrome, including long limbs, with an arm span that is at least 1.03 of the height of the individual, and a crowded oral maxilla, sometimes with a ...
.
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
Duplication, duplicate, and duplicator may refer to:
Biology and genetics
* Gene duplication, a process which can result in free mutation
* Chromosomal duplication, which can cause Bloom and Rett syndrome
* Polyploidy, a phenomenon also known ...
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
Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role and also for ...
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 (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
.
A gene knockout experiment of the mouse homologue of
ZDHHC13 showed hair loss, severe
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
, and systemic
amyloidosis
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...
, both of
AL and
AA depositions.
Human proteins containing this domain
ZDHHC1;
ZDHHC2;
ZDHHC3;
ZDHHC4;
ZDHHC5;
ZDHHC6;
ZDHHC7;
ZDHHC8;
ZDHHC9;
ZDHHC11;
ZDHHC11B;
ZDHHC12;
ZDHHC13;
ZDHHC14;
ZDHHC15;
ZDHHC16;
ZDHHC17;
ZDHHC18;
ZDHHC19;
ZDHHC20;
ZDHHC21;
ZDHHC22;
ZDHHC23;
ZDHHC24;
See also
*
Palmitoylation
Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically lipid bilayer, memb ...
*
Palmitic acid
Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid with a 16-carbon chain. It is the most common saturated fatty acid found in animals, plants and microorganisms.Gunstone, F. D., John L. Harwood, and Albert J. Dijkstra. The Li ...
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
* {{ELM, MOD_SPalmitoyl_4
Protein domains