GAK (protein)
Encyclopedia
Cyclin G-associated kinase (GAK) is a serine/threonine kinase that in humans is encoded by the GAK gene
.
s, the cell cycle
is governed by cyclin-dependent protein kinase
s (CDKs), whose activities are regulated by cyclin
s and CDK inhibitors in a diverse array of mechanisms that involve the control of phosphorylation
and dephosphorylation of Ser, Thr or Tyr residues. Cyclins are molecules that possess a consensus domain called the 'cyclin box.' In mammalian cells, 9 cyclin species have been identified, and they are referred to as cyclins A through I. Cyclin G
is a direct transcriptional target of the p53
tumor suppressor gene product and thus functions downstream of p53. GAK is an association partner of cyclin G and CDK5
.
Cyclin G-associated kinase received its name because it immunoprecipitated with cyclin G though it now appears to not be associated with it. Cyclin G-associated kinase is homologous in function to the protein auxilin which when in association with Hsc70 uncoats clathrin in neuronal cells. However, the location of Cyclin G-associated kinase is not in the brain but near the trans-Golgi network of non-neuronal cells such as those found in the liver and testes. GAK is also known to be associated with focal adhesions
though the exact relationship between the two is unknown.
Cyclin G-associated kinase is a two domain cystolic protein. The domain of interest is the C-terminal domain which consists of three subdomains such as a C-terminal J domain, a clathrin
-binding domain, and a tension-like N-terminal domain. The other domain is the N terminal kinase domain which is a functional Ser/Thr protein kinase. The N-terminal kinase domain is able to phosphorylate histone H1. The subdomain tension-like N terminal function has not yet determined, though the domain shares high homology to the tumor suppressant PTEN
. The key characteristic is the cysteine group which is required for phosphorylation; however the tension-like N terminal subdomain is absent of some important functional residues that PTEN has. The C-terminal J domain is responsible for the interaction with Hsc70, which is a molecular chaperone responsible for the uncoating of clathrin-coated vesicles during endocytosis
. The clathrin-binding domain gathers clathrin into baskets. At pH 7 GAK allows Hsc70 to uncoat clathrin baskets and at pH 6 Hsc70 binds clathrin baskets without uncoating clathrin. Without taking into account GAK’s kinase domain, GAK is 43% identical to auxilin
, a neuronal cell uncoating clathrin cofactor, in its amino acid composition. GAK is 57% homologous to auxilin if conserved residues are included in the comparison. Though similar domains of these two molecules suggest and have similar functions, the proteins carry these functions out in different manners. GAK initiates the assembly of clathrin baskets stochiometrically, but at the different pHs it will either bind the Hsc70 to the baskets or induce the Hsc70 to uncoat the clathrin baskets catalytically which is one difference between auxilin and GAK. This catalytic route explains why less GAK than auxilin is needed to carry out a similar function.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
In all eukaryoteEukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s, the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
is governed by cyclin-dependent protein kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
s (CDKs), whose activities are regulated by cyclin
Cyclin
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...
s and CDK inhibitors in a diverse array of mechanisms that involve the control of phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and dephosphorylation of Ser, Thr or Tyr residues. Cyclins are molecules that possess a consensus domain called the 'cyclin box.' In mammalian cells, 9 cyclin species have been identified, and they are referred to as cyclins A through I. Cyclin G
CCNG1
Cyclin-G1 is a protein that in humans is encoded by the CCNG1 gene.-Interactions:CCNG1 has been shown to interact with P16, Mdm2, PPP2R4 and P53.-Further reading:...
is a direct transcriptional target of the p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
tumor suppressor gene product and thus functions downstream of p53. GAK is an association partner of cyclin G and CDK5
Cyclin-dependent kinase 5
Cell division protein kinase 5 is an enzyme that in humans is encoded by the CDK5 gene. The protein encoded by this gene is part of the cyclin-dependent kinase family.-Physiological Role:...
.
Cyclin G-associated kinase received its name because it immunoprecipitated with cyclin G though it now appears to not be associated with it. Cyclin G-associated kinase is homologous in function to the protein auxilin which when in association with Hsc70 uncoats clathrin in neuronal cells. However, the location of Cyclin G-associated kinase is not in the brain but near the trans-Golgi network of non-neuronal cells such as those found in the liver and testes. GAK is also known to be associated with focal adhesions
Focal adhesion
In cell biology, focal adhesions are specific types of large macromolecular assemblies through which both mechanical force and regulatory signals are transmitted. More precisely, they can be considered as sub-cellular macromolecules that mediate the regulatory effects In cell biology, focal...
though the exact relationship between the two is unknown.
Structure
A structure of GAK was determined using X-ray diffraction to a resolution of 2.10 Å.Cyclin G-associated kinase is a two domain cystolic protein. The domain of interest is the C-terminal domain which consists of three subdomains such as a C-terminal J domain, a clathrin
Clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
-binding domain, and a tension-like N-terminal domain. The other domain is the N terminal kinase domain which is a functional Ser/Thr protein kinase. The N-terminal kinase domain is able to phosphorylate histone H1. The subdomain tension-like N terminal function has not yet determined, though the domain shares high homology to the tumor suppressant PTEN
PTEN (gene)
Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
. The key characteristic is the cysteine group which is required for phosphorylation; however the tension-like N terminal subdomain is absent of some important functional residues that PTEN has. The C-terminal J domain is responsible for the interaction with Hsc70, which is a molecular chaperone responsible for the uncoating of clathrin-coated vesicles during endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. The clathrin-binding domain gathers clathrin into baskets. At pH 7 GAK allows Hsc70 to uncoat clathrin baskets and at pH 6 Hsc70 binds clathrin baskets without uncoating clathrin. Without taking into account GAK’s kinase domain, GAK is 43% identical to auxilin
DNAJC6
Putative tyrosine-protein phosphatase auxilin is an enzyme that in humans is encoded by the DNAJC6 gene.-Further reading:...
, a neuronal cell uncoating clathrin cofactor, in its amino acid composition. GAK is 57% homologous to auxilin if conserved residues are included in the comparison. Though similar domains of these two molecules suggest and have similar functions, the proteins carry these functions out in different manners. GAK initiates the assembly of clathrin baskets stochiometrically, but at the different pHs it will either bind the Hsc70 to the baskets or induce the Hsc70 to uncoat the clathrin baskets catalytically which is one difference between auxilin and GAK. This catalytic route explains why less GAK than auxilin is needed to carry out a similar function.