4. PROTEIN PHOSPHORYLATION
Protein phosphorylation wafirst reported in
1906 by Phoebus Levene. He identified
phosphate in protein vitellin.
It is a post-translational modification of protein
in which an amino acid residue is
phosphorylated by a protein kinase by the
addition of covalently bound phosphate group.
It alters the structural conformation of a protein
, causing it to become activated, deactivated or
modifying its function.
5. Mechanism of Phosphorylation
ATP binds to the active site of the
kinase.
Binding of the substrate to the active
site.
Phosphorylation (γ-phosphate of ATP
is transferred to a Ser, Thr or Tyr
residue of the substrate/protein)
Substrate is released from the kinase.
Release of ADP from active site.
6.
7. BIOLOGICAL THERMODYNAMICS
Phosphorylation of Na+/K
ATPase during the transport of sodium (Na+)
and potassium (K+) ions across the cell
membrane in osmoregulation to
maintain homeostasis of the body's water
content.
8. PROTEIN DEGRADATION
Arginine phosphorylation by McsB
kinase marks proteins for degradation by
a Clp protease. The arginine
phosphorylation system, which is widely
distributed across Gram-positive
bacteria, appears to be functionally
analogous to the eukaryotic ubiquitin–
proteasome system.
9. ENZYME REGULATION (ACTIVATION AND
INHIBITION)
The first example of protein regulation by
phosphorylation was glycogen phosphorylase. Eddie
Fisher and Ed Krebs described how phosphorylation of
glycogen phosphorylase b converted it to the active
glycogen phosphorylase a. It was soon discovered that
glycogen synthase, another metabolic enzyme, is
inactivated by phosphorylation.
Phosphorylation of the enzyme GSK-3 by AKT (Protein
kinase B) as part of the insulin signaling pathway.
Phosphorylation of Src tyrosine kinase (pronounced
"sarc") by Csk (C-terminal Src kinase) inactivates Src by
inducing a conformational change which masks its kinase
domain.
10. PROTEIN – PROTEIN
INTERACTION
Phosphorylation of the cytosolic components
of NADPH oxidase, a large membrane-bound,
multi-protein enzyme present in phagocytic
cells, plays an important role in the regulation
of protein-protein interactions in the enzyme.
11. RECEPTOR TYROSINE KINASES
The AXL receptor tyrosine kinase, showing the symmetry of the
dimerized receptors
While tyrosine phosphorylation is found in relatively low
abundance, it is well studied due to the ease of purification of
phosphotyrosine using antibodies. Receptor tyrosine kinase are
an important family of cell surface receptors involved in the
transduction of extracellular signals such as hormones, growth
factors, and cytokines. Binding of a ligand to a monomeric
receptor tyrosine kinase stabilizes interactions between two
monomers to form a dimer, after which the two bound receptors
phosphorylate tyrosine residues in trans. Phosphorylation and
activation of the receptor activates a signaling pathway through
enzymatic activity and interactions with adaptor
proteins.[20] Signaling through the epidermal growth factor
receptor (EGFR), a receptor tyrosine kinase, is critical for the
development of multiple organ systems including the skin, lung,
heart, and brain. Excessive signaling through the EGFR
pathway is found in many human cancers.
12. CYCLIN DEPENDENT KINASE
Cyclin-dependent kinases (CDKs) are serine-threonine
kinases which regulate progression through the
eukaryotic cell cycle. CDKs are catalytically active only
when bound to a regulatory cyclin. Animal cells contain at
least nine distinct CDKs which bind to various cyclins
with considerable specificity. CDK inhibitors (CKIs) block
kinase activity in the cyclin-CDK complex to halt the cell
cycle in G1 or in response to environmental signals or
DNA damage. The activity of different CDKs activate cell
signaling pathways and transcription factors that regulate
key events in mitosis such as the G1/S phase transition.
Earlier cyclin-CDK complexes provide the signal to
activate subsequent cyclin-CDK complexes.
