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Intrinsically disordered proteins: A conversation with Rohit Pappu
Date:9/20/2012

to differentiate, to die, to regenerate, or to go quiet ,and these decisions are controlled by regulatory networks. The integrators in the networks are predominantly disordered regions.

So the question is: Will mutations in those regions give rise to unwarranted cellular phenotypes and hence diseases, such as cardiovascular disorders, cancer and neurodegeneration? The answer is absolutely yes.

But what we are learning is that mutations in disordered regions don't necessarily generate a deleterious phenotype because disordered regions are fairly unconstrained compared to structured regions. So these regions are also engines of robustness.

They're more robust to mutation?

At least the one study that looked at cancer mutation would suggest that. It showed that cancer-associated mutations partition toward structured regions of proteins, not toward disordered regions.

Do you think the new awareness of disordered proteins will lead to medical breakthroughs?

Maybe. If I tell you that a disordered protein is at the hub of a network, then it stands to reason that targeting the hub with a drug gives you a ready-made way of controlling a cellular decision.

The only problem is that we don't quite know what it means to target a hub. If a protein has a very precise shape we know how to target it: it's like designing a key for a lock. But if a protein is disordered we have to understand what that means for that particular hub. We also have to be aware that anything that changes the hub will change a range of downstream processes, pathways and cellular decisions.

Nonetheless many people now are talking about these disordered proteins as druggable targets.

Together with Peter Tompa, another of the field's founders, you organized a Gordon Research Conference on disordered proteins this summer. This was a chance for the leading scientists in the field to explore their thoughts off the re
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Contact: Diana Lutz
dlutz@wustl.edu
314-935-5272
Washington University in St. Louis
Source:Eurekalert

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