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Protein Folding

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Folding and Characterization of a Bio-responsive Robot from DNA Origami

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Sequence-function relationships in folding upon binding.

Christopher Eginton¹, Saranga Naganathan, Dorothy Beckett

¹Department of Chemistry & Biochemistry, University of Maryland, College Park, Maryland, 20742.

Protein Science : a Publication of the Protein Society

|November 20, 2014

Summary

Protein folding and function are linked, with optimal hydrophobic side chain packing crucial for ligand-induced disorder-to-order transitions in Escherichia coli BirA. Sequence divergence is possible in these functionally important protein segments.

Keywords:

folding upon binding hydrophobic packing isothermal titration calorimetry kinetics sedimentation equilibrium

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Area of Science:

Biochemistry and Molecular Biology
Protein Folding and Dynamics
Enzyme Mechanisms

Background:

Protein folding coupled to ligand binding is a common biological mechanism.
The rules governing protein folding stability may or may not apply to ligand-linked folding transitions.
The Escherichia coli protein BirA undergoes a disorder-to-order transition upon binding biotinoyl-5'-AMP (bio-5'-AMP).

Purpose of the Study:

To investigate the relationship between sequence, function, and ligand-linked folding in protein segments.
To determine if established protein folding rules are relevant to ligand-linked folding transitions.
To elucidate the role of hydrophobic interactions in the disorder-to-order transition of BirA.

Main Methods:

Equilibrium and kinetic measurements of BirA variants with alanine substitutions in the hydrophobic network.
Analysis of functional perturbations, ligand binding, and allosteric activation of protein association.
Assessment of the impact of substitutions on ligand-linked folding transitions.

Main Results:

Single alanine substitutions in the hydrophobic network caused significant functional disruptions.
Multiple substitutions exhibited highly non-additive effects on protein function and folding.
Substitutions disrupted the ligand-linked disorder-to-order folding transition of BirA.

Conclusions:

Optimal packing of hydrophobic side chains is essential for ligand-binding-induced disorder-to-order folding.
Similar to general protein folding, specific residue combinations can achieve functional hydrophobic packing.
This implies that functionally important protein segments involved in binding-coupled folding can tolerate sequence divergence.