Dock9 also known as Zizimin1, is a large (~230 kDa) 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...

 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-D 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 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. Dock9 activates the small G protein Cdc42

CDC42

Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...

.

Discovery

Dock9 was discovered using an affinity proteomic approach designed to identify novel activators of the small G protein Cdc42 in fibroblast

Fibroblast

A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s. Subsequent northern blot

Northern blot

The northern blot is a technique used in molecular biology research to study gene expression by detection of RNA in a sample. With northern blotting it is possible to observe cellular control over structure and function by determining the particular gene expression levels during differentiation,...

 analysis revealed that Dock9 is expressed primarily in the brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

, heart

Heart

The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

, skeletal muscle

Skeletal muscle

Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

, kidney

Kidney

The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, placenta

Placenta

The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

 and lung

Lung

The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

. Lower levels were detected in the colon

Colon (anatomy)

The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...

, thymus

Thymus

The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....

, liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, small intestine

Small intestine

The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

 and in leukocytes from peripheral blood.

Structure and Function

Dock9 shares a similar structure of two core domains

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...

 (known as DHR1

DHR1 domain

DHR1 , also known as CZH1 or Docker1, is a protein domain of approximately 200-250 amino acids that is present in the DOCK family of signalling proteins. This domain binds phospholipids and so may assist in recruitment to cellular membranes. There is evidence that this domain may also mediate...

 and DHR2

DHR2 domain

DHR2 , also known as CZH2 or Docker2, is a protein domain of approximately 450-550 amino acids that is present in the DOCK family of proteins. This domain functions as a guanine nucleotide exchange factor domain for small G proteins of the Rho family...

) which are shared by all DOCK family members. The C-terminal DHR2 domain functions as an atypical GEF domain for small G proteins (see Dock180: structure and function) and the DHR1 domain is known, in some DOCK-A/B/C subfamily proteins, to be involved in their recruitment to the plasma membrane. Unlike DOCK-A/B/C proteins DOCK-D proteins (including Dock9) contain an N-terminal pleckstrin homology (PH) domain which mediates their recruitment to the membrane. Dock9, along with other DOCK-C/D subfamily members, can activate Cdc42 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 in vivo

In vivo

In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

via its DHR2 domain. However, Dock9 adopts an autoinhibitory conformation which masks the DHR2 domain in its resting state. The mechanism by which this autoinhibition is overcome is still unclear although in some other DOCK proteins, which also undergo autoinhibition, it requires an interaction with 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 such as 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...

. Dock9 has also been reported to dimer

Protein dimer

In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

ise, under resting conditions, via its DHR2 domains and this study suggests that other DOCK family proteins may also behave in the same way. Recent analysis of a chromosomal

Chromosome

A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

 region associated with susceptibility to bipolar disorder

Bipolar disorder

Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...

 revealed that single nucleotide polymorphism

Single nucleotide polymorphism

A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...

s in the DOCK9 gene contribute to the risk and severity of this condition.

Further reading