Regulation by reversible protien phosphorylation

Content
Regulation of Gene Expression 3. A Variety of Mechanisms in Eukaryotes
Regulation at Transcription Level
Activation of transcription
Britten-Davidson model for unit of transcription
Gene battery
Chromosomal proteins and gene expression
Repression of transcription 
Specific DNA sequences controlling transcription
Transgenic plants to study regulatory sequences
Modification of DNA sequences and their transcripts in gene expression
Alternative splicing of transcripts
Regulation at translation level
Activation and repression of translation
Masked mRNA in eggs of sea urchin and Xenopus
Regulation by gene re-arrangement
Expression of immunoglobulin genes
Yeast mating type switching
Trypanosome surface antigen (VSG) switching
Synthesis of mRNA in pieces in VSG genes in trypanosome
Regulation by reversible phosphorylation
Signal transduction and second messengers
Proteins and peptide hormones and gene expression
Steroid hormones and gene expression
Interferon stimulated gene expression (without a second messenger)
Cell surface receptors in cholesterol metabolism and drug production
Ubiquitin protein and regulation of heat shock genes
Regulation by Reversible Protein Phosphorylation
The 1992 Nobel Prize for physiology and medicine was awarded to Prof. Edwin G. Krebs and Prof. Edmond H. Fisher, both of University of Washington, Seattle, U.S.A. for their pioneering work on 'reversible protein phosphorylation as a biological regulatiory mechanism'. Phosphorylation of proteins has been shown to affect transcription, translation, cell division, cell growth, cell differentiation, cell transformation and many other cellular processes. Regulation of enzyme activity by reversible phosphorylation has several advantages over de novo synthesis of enzyme. The response is fast and the signal gets amplified. One molecule of kinase can phosphorylate several molecules of an enzyme. Activity of several non-enzymatic proteins like transcription factors is also regulated by reversible phosphorylation. It is estimated that a eukaryotic cell has about 1000 genes for different protein kinases (for phosphorylation) and perhaps same number of genes for protein phosphatases (for dephosphorylation).

The first protein (enzyme in this case), whose activity was shown to be regulated by phosphorylation was glycogen phosphorylase (involved in breakdown of glycogen in muscle and liver). This enzyme exists in two forms, phosphorylase a (not dependent on AMP for its activity) and phosphorylase b (dependent on AMP for its activity). Reversible phosphorylation leading to interconversion of these two forms has been shown. Almost all of the enzyme is in an inactive 'b' form in resting muscle, which gets converted to the active 'a' form, when the level of hormone, epinephrine, increases in the blood (Fig. 37.21).
 
Reversible phosphorylation of phosphorylase enzyme at serine residue causing conformational changes in the enzyme.
Fig. 37.21. Reversible phosphorylation of phosphorylase enzyme at serine residue causing conformational changes in the enzyme.

Phosphorylation of protein occurs on many residues, but mainly serine (Ser; 90-95%), threonine (Thr; 5-10%) and tyrosine (Tyr; <10%) are phosphorylated. Phosphorylation does not always lead to increase in enzyme activity, and in some cases may actually lead to decrease in activity (e.g. glycogen synthase). Sometimes positive and negative regulatory phosphorylation sites are present in the same enzyme, so that same enzyme may need two kinases and two phosphatases.