Autophosphorylation
Autophosphorylation is a type of
Function
Protein kinases, many of which are regulated by autophosphorylation, are vital in controlling the cellular proliferation, differentiation, metabolism, migration and survival. Mutations in the genes encoding them or their potential activators or repressors can affect any number of functions within an organism.[3][4]
Phosphorylation is easily reversed by phosphatases. Therefore, it is an effective method of turning 'on' and 'off' kinase activity. Because of this it is recognized as an essential process in cell signaling.[3]
Addition of a negatively charged phosphate group brings about a change in the microenvironment that may lead to attraction or repulsion of other residues or molecules.[3][4] The result may be a conformational change to expose or hide catalytic or allosteric seats from the surface.[3]
If the phosphorylated residue resides within the catalytic seat itself, it may facilitate or prevent substrate binding by means of charge-interaction, or by providing or preventing complementary shapes necessary for molecular recognition.
Binding of effector molecules may be affected in a similar manner if the phosphorylated residue makes part of the
Process and structure
Kinases are either phosphorylated on serine and/or threonine residues, or solely on tyrosine residues.[5] This serves as a means to classify them as either Ser/Thr- or Tyr-kinases. Several residues within the
- Tyr phosphorylation sites in juxtamembrane regions:
- Tyr phosphorylation sites in kinase insert regions:
- Tyr phosphorylation sites in activation loops:
- Ser/Thr phosphorylation sites in activation loops:
- N or C terminal tails Ser/Thr phosphorylation sites:
In general, the structures of the phosphorylation of internal loops involve important domain-domain contacts that have been confirmed by site-directed mutagenesis, while the phosphorylation of positions in the N or C terminal tails more than 10 amino acids away from the kinase domain do not involve important domain-domain contacts away from the substrate binding site.[6]
Signaling pathways and trans-autophosphorylation
Among a number of various molecules,
Examples of RTKs which undergo autophosphorylation
Epidermal growth factor receptor
An example of RTKs that undergo autophosphorylation is the
Insulin receptors
Another example is the binding of
Cancer
Src kinases
The Src-family kinases are examples of proteins that utilize autophosphorylation to sustain their activated states.[3] Src kinases are involved in intracellular signaling pathways that influence cell growth and cell adhesion strength. The latter contributes to the control of cell migration. In this way, src-kinase deregulation can enhance tumor growth and invasive potential of cancer cells.[2] The activity of src kinases is regulated by both phosphorylation and intramolecular interactions involving the SH2 and SH3 domains. The probable activation mechanism of src kinase in cancer is as follows:
- 1. The src kinase is kept in an inactive form through the binding of SH2 to a phosphotyrosine
- 2. Dephosphorylation of tyr-527 releases SH2 as well as SH3 domain.
- 3. Subsequent autophosphorylation of tyr-416 activates the kinase.
- 4. The constitutive activation of src kinase observed in cancer can be due to deletion of tyr-527, displacement of SH3 and SH2-mediated interactions by high affinity ligands with constantly autophosphorylated tyr-416.[2](Fig. 2).
Ataxia telangiectasia mutated kinase (ATM kinase)
ATM kinase, a member of the
See also
References
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