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A cross-strand Trp-Trp pair stabilizes the hPin1 WW domain at the expense of function

Academic Article
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Overview

authors

  • Jager, M.
  • Dendle, M.
  • Fuller, A. A.
  • Kelly, Jeffery

publication date

  • October 2007

journal

  • Protein Science  Journal

abstract

  • Using the human Pin1 WW domain (hPin1 WW), we show that replacement of two nearest neighbor non-hydrogen-bonded residues on adjacent beta-strands with tryptophan (Trp) residues increases beta-sheet thermodynamic stability by 4.8 kJ mol(-1) at physiological temperature. One-dimensional NMR studies confirmed that introduction of the Trp-Trp pair does not globally perturb the structure of the triple-stranded beta-sheet, while circular dichroism studies suggest that the engineered cross-strand Trp-Trp pair adopts a side-chain conformation similar to that first reported for a designed "Trp-zipper" beta-hairpin peptide, wherein the indole side chains stack perpendicular to each other. Even though the mutated side chains in wild-type hPin1 WW are not conserved among WW domains and compose the beta-sheet surface opposite to that responsible for ligand binding, introduction of the cross-strand Trp-Trp pair effectively eliminates hPin1 WW function as assessed by the loss of binding affinity toward a natural peptide ligand. Maximizing both thermodynamic stability and the domain function of hPin1 WW by the above mentioned approach appears to be difficult, analogous to the situation with loop 1 optimization explored previously. That introduction of a non-hydrogen-bonded cross-strand Trp-Trp pair within the hPin1 WW domain eliminates function may provide a rationale for why this energetically favorable pairwise interaction has not yet been identified in WW domains or any other biologically evolved protein with known three-dimensional structure.

subject areas

  • Amino Acid Sequence
  • Circular Dichroism
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptidylprolyl Isomerase
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Spectrometry, Fluorescence
  • Thermodynamics
  • Tryptophan
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Research

keywords

  • Trp-zipper
  • beta-sheet
  • protein engineering
  • secondary structure propensity
  • wW domain
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Identity

PubMed Central ID

  • PMC2204138

International Standard Serial Number (ISSN)

  • 0961-8368

Digital Object Identifier (DOI)

  • 10.1110/ps.072904107

PubMed ID

  • 17766376
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Additional Document Info

start page

  • 2306

end page

  • 2313

volume

  • 16

issue

  • 10

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