1. Signaling by G protein coupled receptors (GPCRs) is generally very rapid (hal

Question

1. Signaling by G protein coupled receptors (GPCRs) is generally very rapid (half-time for changes in downstream signaling mediators can be milliseconds) while signaling by tyrosine kinases is generally quite a bit slower (half-time for recruitment of SH2 effector proteins of several minutes). What molecular mechanisms might explain this difference in response dynamics?

2. The erythropoietin (Epo) receptor of a famous long-distance runner is sequenced and it is found to have a mutation at a Ser residue known to be phosphorylated upon stimulation with Epo. The Ser residue is converted to Ala in the mutant allele. How might this mutation be linked to this person's athletic endurance?

Explanation / Answer

2) Signalling of erytropoietin, through JAK-STAT pathway, by binding to its receptor, EPOR promotes proliferation and differentiation of progenitor erythroid cells leading to the development of Red blood cells. Erythropoietin receptor has conserved sequence, Tryptophan-serine-X-tryptophan-serine (WSXWS) located in the C-terminal domain; where ligand (erythropoietin) binds leading to the activation of the receptor. Mutation in the sequence of EPOR disrupts signalling pathway. For example - replacement of one serine by alanine affects the phosphorylation activity on tyrosineand hence disrupts signalling pathway but addition of three alanine residues restores its wild type activity.

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