DOCK3
Encyclopedia
Dock3 also known as MOCA (modifier of cell adhesion) and PBP (presenilin-binding protein), is a large (~180 kDa) protein
involved in intracellular
signalling networks. It is a member of the DOCK-B subfamily of the DOCK
family of guanine nucleotide exchange factor
s (GEFs) which function as activators of small G protein
s. Dock3 specifically activates the small G protein Rac
.
(a transmembrane protein
which is mutated in early onset Alzheimer's disease
). Dock3 is specifically expressed in neurones (primarily in the cerebral cortex
and hippocampus
).
(GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate
(GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock3 exhibits the same domain
arrangement as Dock180 (a member of the DOCK-A subfamily and the archetypal member of the DOCK family) and these proteins share a considerable (40%) degree of sequence similarity.
, which in Dock180 binds ELMO
(a family of adaptor protein
s which mediate recruitment and efficient GEF activity of Dock180), and a C-terminal proline
-rich region which, in Dock180, binds the adaptor protein CRK
.
. Dock3 has not been shown to interact with Rac3
, another Rac protein which is expressed in neuronal cells, and this may be because Rac3 is primarily located in the perinuclear region. In fact, Rac1 and Rac3 appear to have distinct and antagonistic roles in these cells. Dock3-mediated Rac1 activation promotes reorganisation of the cytoskeleton
in SH-SY5Y
neuroblastoma
cells and primary cortical
neurones as well as morphological
changes in fibroblasts. It has also been shown to regulate neurite
outgrowth and cell-cell adhesion
in B103 and PC12 cells
.
resembling attention-deficit hyperactivity disorder
(ADHD).
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...
involved in intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
signalling networks. It is a member of the DOCK-B subfamily of the DOCK
DOCK (protein)
DOCK is a family of related proteins involved in intracellular signalling networks. Studies to date suggest that this family act as guanine nucleotide exchange factors for small G proteins of the Rho family, such as Rac and Cdc42...
family of guanine nucleotide exchange factor
Guanine nucleotide exchange factor
Guanine nucleotide exchange factors activate monomeric GTPases by stimulating the release of guanosine diphosphate to allow binding of guanosine triphosphate . A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity...
s (GEFs) which function as activators of small G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
s. Dock3 specifically activates the small G protein Rac
Rac (GTPase)
Rac is a subfamily of the Rho family of GTPases, small signaling G proteins .The subgroup include:*Rac1*Rac2*Rac3*RhoG...
.
Discovery
Dock3 was originally discovered in a screen for proteins that bind presenilinPresenilin
Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase intramembrane protease complex...
(a transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
which is mutated in early onset Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
). Dock3 is specifically expressed in neurones (primarily in the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
).
Structure and function
Dock3 is part of a large class of proteins (GEFs) which contibrute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to Guanosine diphosphateGuanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....
(GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
(GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock3 exhibits the same domain
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...
arrangement as Dock180 (a member of the DOCK-A subfamily and the archetypal member of the DOCK family) and these proteins share a considerable (40%) degree of sequence similarity.
Regulation of Dock3 activity
Since Dock3 shares the same domain arrangement as Dock180 it is predicted to have a similar array of binding partners, although this has yet to be demonstrated. It contains an N-terminal SH3 domainSH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
, which in Dock180 binds ELMO
ELMO (protein)
ELMO is a family of related proteins involved in intracellular signalling networks. These proteins have no intrinsic catalytic activity and instead function as adaptors which can regulate the activity of other proteins through their ability to mediate protein-protein interactions.This family...
(a family of adaptor protein
Adaptor protein
Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...
s which mediate recruitment and efficient GEF activity of Dock180), and a C-terminal 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...
-rich region which, in Dock180, binds the adaptor protein CRK
CRK (gene)
Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
.
Signalling downstream of Dock3
Dock3 GEF activity is directed specifically at Rac1RAC1
Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
. Dock3 has not been shown to interact with Rac3
Rac3
Rac3 is a small monomeric GTP-binding protein G protein and is an important component of intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RAC3....
, another Rac protein which is expressed in neuronal cells, and this may be because Rac3 is primarily located in the perinuclear region. In fact, Rac1 and Rac3 appear to have distinct and antagonistic roles in these cells. Dock3-mediated Rac1 activation promotes reorganisation of the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
in SH-SY5Y
SH-SY5Y
-History:The cell line SH-SY5Y is a human derived neuroblastoma cell line, thrice-cloned originally from SK-N-SH and first reported in 1978. A neuroblast-like subclone of SK-N-SH, named SH-SY, was subcloned as SH-SY5, which was subcloned again as SH-SY5Y...
neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
cells and primary cortical
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
neurones as well as morphological
Morphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
changes in fibroblasts. It has also been shown to regulate neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
outgrowth and cell-cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
in B103 and PC12 cells
PC12 cells
PC12 is a cell line derived from a pheochromocytoma of the rat adrenal medulla. PC12 cells stop dividing and terminally differentiate when treated with nerve growth factor...
.
Dock3 in neurological disorders
The first indication that Dock3 might be involved in neurological disorders came when Dock3 was shown to bind to presenilin, a transmembrane enzyme involved in the generation of beta amyloid (Aβ), accumulation of which is an important step in the development of Alzheimer's disease. Dock3 has been shown to undergo redistribution and association with neurofibrillary tangles in brain samples from Alzheimers patients. A mutation in Dock3 was also identified in a family displaying a phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
resembling attention-deficit hyperactivity disorder
Attention-deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
(ADHD).