Dock3 (
Dedicator
of
cyto
kinesis 3), 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
A dock (from Dutch language, Dutch ''dok'') is the area of water between or next to one or a group of human-made structures that are involved in the handling of boats or ships (usually on or near a shore) or such structures themselves. The ex ...
family of
guanine nucleotide exchange factors (GEFs) which function as activators of small
G proteins. Dock3 specifically activates the small G protein
Rac
RAC or Rac may refer to:
Organizations
* Radio Amateurs of Canada
* RATCH-Australia Corporation, electricity generator
* Refugee Action Collective (Victoria), Melbourne, Australia
* Religious Action Center of Reform Judaism, US
* Rent-A-Center, ...
.
Discovery
Dock3 was originally discovered in a screen for proteins that bind
presenilin
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset ...
(a
transmembrane protein which is mutated in early onset
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
).
Dock3 is specifically expressed in
neurones (primarily in the
cerebral cortex and
hippocampus).
Structure and function
Dock3 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to
Guanosine diphosphate (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
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
**Domain of definition of a partial function
**Natural domain of a partial function
**Domain of holomorphy of a function
* Do ...
arrangement as
Dock180
Dock180, (Dedicator of cytokinesis) also known as DOCK1, is a large (~180 kDa) protein involved in intracellular signalling networks. It is the mammalian ortholog of the ''C. elegans'' protein CED-5 and belongs to the DOCK family of Guanine nucl ...
(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
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
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
SH3 domain, which in Dock180 binds
ELMO (a family of
adaptor proteins which mediate recruitment and efficient GEF activity of Dock180), and a
C-terminal 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 ...
-rich region which, in Dock180, binds the adaptor protein
CRK
Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the ''CRK'' gene.
The CRK protein participates in the Reelin signaling cascade downstream of DAB1.
Function
Adapter molecule crk is a member of ...
.
Downstream signalling
Dock3 GEF activity is directed specifically at
Rac1. 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
SH-SY5Y is a human derived cell line used in scientific research. The original cell line, called SK-N-SH, from which it was subcloned was isolated from a bone marrow biopsy taken from a four-year-old female with neuroblastoma. SH-SY5Y cells are o ...
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
PC12 is a cell line derived from a pheochromocytoma of the rat adrenal medulla, that have an embryonic origin from the neural crest that has a mixture of neuroblastic cells and eosinophilic cells.
Background
This cell line was first cultured ...
.
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 patients with Alzheimer's disease.
A mutation in Dock3 was also identified in a family displaying a
phenotype resembling
attention-deficit hyperactivity disorder (ADHD).
References
Further reading
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