Dedicator of cytokinesis protein 9 (Dock9), also known as Zizimin1, is a large (~230 kDa)

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

encoded in the human by the ''DOCK9'' gene, involved in

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

signalling networks. It is a member of the DOCK-D subfamily of the

DOCK The word dock () in American English refers 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). In British English, the term is not used the same way as in American Engl ...

family of

guanine nucleotide exchange factor Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structu ...

s that function as activators of

small G-protein Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrim ...

s. Dock9 activates the small G protein

Cdc42 Cell division control protein 42 homolog (Cdc42 or CDC42) is a protein that in humans is encoded by the ''CDC42'' gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in ''S. cerevisiae'' (yeast) as a mediator of ...

Discovery

Dock9 was discovered using an affinity

proteomic Proteomics is the large-scale study of proteins. Proteins are vital macromolecules of all living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replicatio ...

approach designed to identify novel activators of the small G protein Cdc42 in

fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

s. Subsequent

northern blot The northern blot, or RNA blot,Gilbert, S. F. (2000) Developmental Biology, 6th Ed. Sunderland MA, Sinauer Associates. is a technique used in molecular biology research to study gene expression by detection of RNA (or isolated mRNA) in a sample.Ke ...

analysis revealed that Dock9 is expressed primarily in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

and

lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...

. Lower levels were detected in the colon,

thymus The thymus (: thymuses or thymi) is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus ...

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...

and in

leukocyte White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

s from peripheral blood.

Structure and function

Dock9 shares a similar structure of two core domains (known as DHR1 and DHR2), which are shared by all DOCK family members. The

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy 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 t ...

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 The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. Unlike DOCK-A/B/C proteins DOCK-D proteins (including Dock9) contain an N-terminal pleckstrin homology (PH) domain that mediates their recruitment to the membrane. Dock9, along with other DOCK-C/D subfamily members, can activate Cdc42 ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' via its DHR2 domain. However, Dock9 adopts an autoinhibitory conformation that 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 proteins such as

ELMO Elmo is a Muppet character on the children's television show ''Sesame Street''. A furry red monster who speaks in a high-pitched falsetto voice and frequently refers to himself in the third person, he hosts the last full 15-minute segmen ...

. Dock9 has also been reported to dimerise, 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 A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most importa ...

region associated with susceptibility to

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

revealed that

single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

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

Discovery

Structure and function

References

Further reading