Serine/Threonin Protein Kinases Flashcards
How are kinases classified, and what may complicate this classification?
Kinases may be classified by:
1 The residues they phosphorylate (Ser/Thr or Tyr)
2 Their substrate protein
3 Their activating stimulus
4 Their phylogenic (family) relationship
Some kinases have two active sites that are found in different families or classifications, and thus do not fall into any single class.
Are kinases or phosphatases more abundant in the cell, and what does their relative ratio indicate about regulation of their activities?
Kinases are far more abundant than phosphatases. This indicates that kinases are generally more regulated and specific than phosphatases, which must be constitutively active and somewhat non-specific to keep up with the rates of phosphorylation. There is some regulation of phosphatases as well, so it is not such a simple relationship.
Why can most kinases phosphorylate Serine/Threonine, but not Tyrosine, and vis versa, but few that can phosphorylate both? How does phosphorylation actually occur?
Serine and Threonine have similar sizes and structures, while Tyrosine is a much larger amino acid. The hydroxyl groups on these amino acids nucleuphilicly attack the gamma phosphate group of ATP on the kinase.
What purposes do the activation loop and glycine rich loop serve in kinases?
In many kinases, the activation loop must be phosphorylated to activate the kinase. However, some kinases do not need this phosphorylation to be activated. The glycine rich loop clamps down on the ATP to position the gamma phosphate. Release of the resulting ADP from the glycine rich loop is the slow step of the kinase cycle.
What is one problem of developing drugs that target kinases and how can this be avoided?
The active sites of kinases are highly conserved across the kinase families. A drug that binds to the active site of one kinase (PKC) actually inhibits 3/4 of all kinases. Drugs that bind elsewhere and affect the conformation of at least 2 of these structures inhibit the kinase: ATP binding pocket, glycine loop, activation loop, C helix.
How are many kinases regulated?
Via phosphorylation or dephosphorylation by other kinases, or by autophosphorylation (PKA).
Why are MAP kinase pathways often called cascades, and why is this generally a misnomer?
MAP kinases are generally phosphorylated in a long chain of phosphorylation events included MAP kinase kinases, and MAP kinase kinase kinases, suggesting a cascade-like process of activation. However, most of these signaling events occur in 1:1 fashion and do not involve the signal amplification implied by “cascades”.
In what sorts of diseases or conditions would the kinase pathways present in T-cells be of therapeutic interest?
Autoimmune diseases and post-grafting surgery immune response. Knowing the specific targetable pathways would be very useful in designing treatments. Rapamycin and cyclosporin both effect these pathways.
How are CNS neural synapses strengthened by glutamate signaling?
Glutamate is the neurotransmitter in CNS synapses and interacts with two types of receptors. NMDA type allow Ca2+ influx, AMPA type allow Na+ influx. NMDA are initially blocked by Mg2+ but depolarization caused by AMPA Na+ influx opens the NMDA channels to Ca2+. Ca2+ leads to “long term potentiation” involving increased # of AMPA receptors and stronger neural signaling.
