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Dynamic activation of protein function

NSF Award:

Structural and Dynamic Studies of Catabolite Activator Protein Complexes  (Rutgers University New Brunswick)

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Changes in protein structure can substantially effect protein regulation, a critical activity during cellular processes. To date, researchers considered structural changes the only way to regulate binding or enzymatic protein activities. However, research by Charalampos Kalodimos and a team at Rutgers University has shown that modifications to the internal dynamics of proteins can produce dramatic changes in protein activity. For instance, alterations in protein flexibility can determine whether binding interactions occur.

These findings will enrich and reshape understanding of the mechanisms that underpin fundamental biological processes, such as allosteric regulation (the regulation of an enzyme or other protein at the active site of an adjoining protein subunit). The teams' conclusions are important because allosteric interactions are widespread in nature and regulate most cellular processes.

To understand the role of protein flexibility in regulating protein activity, the researchers studied different states of the Escherichia coli catabolite activator protein (CAP), a universal transcriptional activator that regulates the expression of over 200 genes. CAP provides a classic model system for structural and mechanistic studies of transcription activation.

Using nuclear magnetic resonance spectroscopy and thermodynamic tools, the researchers demonstrated how changes in fast and slow internal dynamics regulate binding activity in a way that cannot be predicted based on a protein's ground-state structure. The results suggest that changes in protein dynamics may be the dominant force driving allosteric interactions.

Postdoctoral, graduate and undergraduate students participated in the project, experiencing first-hand, state-of-the-art methodologies to simultaneously characterize high-resolution structures and atomic dynamic properties of key biological systems.

The results were reported in Nature.

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  • changes in the internal dynamics of proteins can cause dramatic changes in protein activity
A protein demonstrates its flexibility. Blue indicates rigidity while red shows flexibility.
Charalampos Kalodimos

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