MM9 - Dynamic Regulation of Protein (iii)

Phosphorylation

reversible

phosphate added to serine, threonine, tyrosine

ratio abundance = 100:10:1

tyrosine = least abundant, but when phosphorylated has greatest effect

tightly regulated

kinases phosphorylate

phosphatases dephosphorylate

clinical targets...

chronic myelogenous leukemia

uncontrolled growth of myeloid cells in bone marrow, accumulate in blood

ABL gene of chromo 9 translocates to BCR gene of chromo 22 to form BCR-ABL (the Philadelphia chromo, abnormal, aggressive, uncontrollable)

BCR-ABL interacts with IL3 R+ drive myeloid cell proliferation

treatment = tyrosine kinase inhibitor (Gleevec, glivec, imitinib, Tasigna)

1st drug designed based on how disease works (rational drug design)

FDA-aproved in record time

many functions

alters function

marks for degradation

alters location

promotes protein-protein interactions

FA modification

functions

membrane anchoring

protein-protein interactions

protein would repel membrane otherwise

reversible

types: farnesylation, myristoylation, palmitoylation, GPI-anchoring

Disregulation

CFTR mutation

can't be localised

loss of phosphorylation site

inactive protein

small GTPase mutation

cancers