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Published on: May 26, 2011
Intrinsically unstructured proteins by design-electrostatic interactions can control binding, folding, and function
Johan Rydberg1, Lars Baltzer, Vijayalekshmi Sarojini
1Department of Chemistry-IFM, Linköping University, 581 83, Linköping, Sweden.
Summary
Designed intrinsically disordered proteins fold into functional structures upon target binding. Electrostatic repulsion at neutral pH can inhibit this folding, offering insights into biological protein dynamics.
Area of Science:
- Protein engineering
- Biochemistry
- Structural biology
Background:
- Intrinsically disordered proteins (IDPs) lack stable tertiary structures in solution but can adopt ordered conformations upon binding to specific targets.
- Understanding the principles governing IDP folding and function is crucial for various biological processes.
Purpose of the Study:
- To design novel intrinsically disordered proteins that undergo conditional folding upon target recognition.
- To investigate the role of electrostatic interactions in modulating the binding and folding behavior of these designed proteins.
- To establish a link between binding, structural transition, and catalytic function.
Main Methods:
- Design and synthesis of intrinsically disordered polypeptides.
- Nuclear Magnetic Resonance (NMR) and Circular Dichroism (CD) spectroscopy to assess protein structure.
- Analytical ultracentrifugation to determine binding stoichiometry and complex formation.
- Introduction and characterization of a catalytic site for ester hydrolysis.
Main Results:
- Designed polypeptides exhibited disordered characteristics in monomeric form and formed stable four-helix bundles upon binding to specific targets.
- Binding resulted in exclusively heterodimer formation at neutral pH, confirmed by analytical ultracentrifugation.
- A catalytically active ester hydrolysis site was introduced, demonstrating structured and active states only in the presence of the target polypeptide.
- Electrostatic repulsion between surface residues was identified as a key factor inhibiting monomer binding and folding at pH 7.
Conclusions:
- Designed IDPs can transition from disordered to ordered states upon specific target binding, enabling function.
- Electrostatic interactions play a significant role in regulating the binding and folding of IDPs, potentially explaining their behavior in biological systems.
- This work provides a framework for understanding how inherent disorder and conditional folding contribute to protein function in biology.
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