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Structure-function-folding relationship in a WW domain.

Marcus Jäger1, Yan Zhang, Jan Bieschke

  • 1Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC265, La Jolla, CA 92037, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 30, 2006
PubMed
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This summary is machine-generated.

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Protein folding barriers in human Pin1 WW domain are primarily caused by functional requirements, not physical folding constraints. Optimizing loop 1 for faster folding sacrifices essential protein-protein interaction capabilities.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Protein Dynamics

Background:

  • Protein folding barriers arise from energetic frustration, sequence variation, and selection pressures.
  • The human Pin1 WW domain's rate-limiting folding step involves its loop 1 substructure.
  • Loop 1 is critical for mediating protein-protein interactions via Pro-rich sequence binding.

Purpose of the Study:

  • To investigate the origins of the folding barrier in the human Pin1 WW domain.
  • To determine if functional requirements or physical folding constraints dictate the folding rate.
  • To assess the impact of loop engineering on folding kinetics and WW domain function.

Main Methods:

  • Protein engineering of loop 1 in the human Pin1 WW domain.
  • Analysis of WW domain folding kinetics and thermodynamic stability.

Related Experiment Videos

  • Ligand-binding studies to evaluate WW domain function.

    • Main Results:

    • Replacing wild-type loop 1 with sequences favoring beta-turn or G1 bulge conformations accelerated folding by an order of magnitude and increased stability.
    • Engineered loops significantly impaired WW domain function, as indicated by ligand-binding studies.
    • The energetic contribution of loop 1 to ligand binding is critical for function, outweighing folding speed and stability benefits.

    Conclusions:

    • The two-state folding barrier of the wild-type human Pin1 WW domain is predominantly driven by functional requirements for ligand binding.
    • Protein function, specifically mediating protein-protein interactions, has evolved at the expense of optimal folding energetics and stability.
    • Loop engineering can enhance folding but compromises the essential biological role of the WW domain.