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How the tilt of a cell-surface receptor prevents cancer
Date:1/31/2013

y subsequently showed that a mutation of one of those amino acidsknown as tryptophan, and symbolized by the letter Wfound at position 515, led to the receptor's permanent activation in mice. Constantinescu and his colleagues predicted then that mutations of W515 would turn up in human cancersand were proved correct by other laboratories and their own studies. "But what remained unclear for the field," says Constantinescu, "was why this tryptophan in particular is so important, why, if you mutate it, TpoR is spontaneously activated."

Biochemical and functional analyses of mutant and normal TpoR conducted by Constantinescu's lab and structural studies of receptors conducted by Smith's lab, established that the tryptophan has a pronounced effect on the function of TpoR through control of the receptor's spatial orientation. "Basically, we found that the tryptophan forces TpoR to tilt," says Constantinescu. "This means that when two normal TpoRs that have not yet been switched on by thrombopoietin come together in the cellular membrane, the tilted coils that normally span the membrane cross each other to form something like an X, not two parallel lines. When parallel, these coils attract each other specifically. Tilting prevents the two coils from contacting each other within the membrane and, in effect, prevents their spontaneous activation."

"If you replace the tryptophan with a variety of amino acids other than tryptophan," explains Constantinescu, "the receptor straightens up. It can then pair up with another TpoReven without thrombopoietin bindingand begin signaling continuously." The result, it would appear, is the unrestrained transmission of proliferative signals and the development of ET and primary myelofibrosis.

This finding is significant for both the basic science of signal transduction and applied cancer research. Tryptophan is found at similar points in some other cell surface receptors, but molecular biologists had presumed tha
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Contact: Rachel Steinhardt
rsteinhardt@licr.org
212-450-1582
Ludwig Institute for Cancer Research
Source:Eurekalert

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