Having no structure can be a good thing
by test2be
Article:
The epidermal growth factor receptor (EGFR) is a transmembrane receptor protein with its extra cellular receptor domain and intracellular kinase domain. After binding its ligand the receptor undergoes a conformational change that promotes dimerization between two EGFR molecules. This active form dimer is then able to phosphorylate its substrates, thus signaling information. Since the downstream targets that are activated by EGFR are involved in cell growth and proliferation it is no surprise that aberrant signaling results in cancer.
There have been many mutations in EGFR linked to cancer, with a prominent mutation being the L843R variant. While it is obvious that this mutations predisposes individuals to develop cancer, the mystery of how this mutation activates the kinase activity has not been solved. Of the many experimental approaches available, the authors of the paper linked to above chose to use computational protein simulations to explore mutational effects.
The first interesting result generated by their models suggested that rather than the two conformational orientations that EGFR is known to occupy there is a third state. They arrived at this conclusion by noticing that the dynamics of drug binding with the protein only occupying the two known configurations was not the same as the drug binding experimentally determined. Once they added in a third configurations, binding kinetics matched the experimental results.
The basis of their theory is that normally the extra cellular domain of EGFR exists in a disordered state. The L843R mutation causes this extracellular domain to become more ordered, and thus more likely to dimerize and activate signaling, just like what would happen with its ligand binds to it. This postulate was shown true by studying the dimerization rates of wild type vs. mutant in experimental studies.
What this means to you…
Since EGFR is mutated in a vast number of cancers, understanding how this mutations causes cellular disturbance is critical to designing drugs to treat these mutations. This new knowledge of predisposition to dimerization will aid not only in the understanding of cancers caused by this mutation, but also by granting a great understanding of receptor signaling in other pathways as well.
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