How kinases work -H Flashcards
What are the conserved and non-conserved parts of RTKs
They have very diverse regulatory domains, however the catalytic domains are highly conserved in their structure, ATP and target protein recognition, and in their mechanism of catalysis.
Kinases overall structure (lobes) and their functions
They are bi-lobed structures, having an N and C lobe.
The ATP and 2 Mg2+ ions make contact with the kinase in the N lobe, where they interact with Gly-rich loop, the hinge region, and the alphaC helix.
The C lobe forms the contacts for the peptide/protein target. It contains the catalytic loop, which coordinates the terminal ATP-gamma-phosphate to be transferred to the target. The HRD (His-Arg-Asp) motif is involved in this. The residues found in the catalytic loop mediate the binding of complementary AAs in the target protein.
The activation loop is also found in the interface between the N and C lobe. It is the trigger for kinase activation. It contains the autophosphorylation residues. Drives the conformational change needed for activation. The activation loop contains the DFG motif. It can be in 2 conformations: DFGin or DFGout, with DFGin being associated with being activated and DFGout with the inactivated conformation. Strong role in antagonist binding.
Kinase architecture and skeletal structure
Hydrophobic residues form the active kinase skeleton. R and C spines.
R is the regulatory spine and C is the catalytic spine.
The C-spine gets completed following ATP binding, where the adenosine of ATP completes it.
The R-spine contains the Phe of the DFG motif.
The hydrophobic alphaF helix of the C-lobe supports this active kinase structure.
Regulation of kinase activation
The regulatory regions of kinases are can also be phosphorylated, such as the binding domains for protein-protein interactions, or binding regions for secondary messengers.
These play a role in dimerisation and transactivation, so phosphorylation can modulate the kinase function and signalling capabilities.
