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Structure-function-folding relationship in a WW domain

Academic Article
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Overview

authors

  • Jager, M.
  • Zhang, Yan Jessie
  • Bieschke, J.
  • Nguyen, H.
  • Dendle, M.
  • Bowman, M. E.
  • Noel, J. P.
  • Gruebele, M.
  • Kelly, Jeffery

publication date

  • 2006

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Protein folding barriers result from a combination of factors including unavoidable energetic frustration from nonnative interactions, natural variation and selection of the amino acid sequence for function, and/or selection pressure against aggregation. The rate-limiting step for human Pin1 WW domain folding is the formation of the loop 1 substructure. The native conformation of this six-residue loop positions side chains that are important for mediating protein-protein interactions through the binding of Pro-rich sequences. Replacement of the wild-type loop 1 primary structure by shorter sequences with a high propensity to fold into a type-I' beta-turn conformation or the statistically preferred type-I G1 bulge conformation accelerates WW domain folding by almost an order of magnitude and increases thermodynamic stability. However, loop engineering to optimize folding energetics has a significant downside: it effectively eliminates WW domain function according to ligand-binding studies. The energetic contribution of loop 1 to ligand binding appears to have evolved at the expense of fast folding and additional protein stability. Thus, the two-state barrier exhibited by the wild-type human Pin1 WW domain principally results from functional requirements, rather than from physical constraints inherent to even the most efficient loop formation process.

subject areas

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Enzyme Stability
  • Humans
  • Kinetics
  • Ligands
  • Molecular Sequence Data
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase
  • Protein Folding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Thermodynamics
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Research

keywords

  • beta-sheet
  • beta-turn
  • ligand binding
  • protein folding
  • protein function
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Identity

PubMed Central ID

  • PMC1502286

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0600511103

PubMed ID

  • 16807295
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Additional Document Info

start page

  • 10648

end page

  • 10653

volume

  • 103

issue

  • 28

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