Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins

Romel B. Perez, Alexander Tischer, Matthew T Auton, Steven T. Whitten

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Molecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intrinsically disordered proteins (IDPs), mediate key signaling pathways suggests that protein structures without cooperative intramolecular interactions may also have the ability to couple local and global structure changes. Presented here are results from experiments that measured and tested the ability of disordered proteins to couple local changes in structure to global changes in structure. Using the intrinsically disordered N-terminal region of the p53 protein as an experimental model, a set of proline (PRO) and alanine (ALA) to glycine (GLY) substitution variants were designed to modulate backbone conformational propensities without introducing non-native intramolecular interactions. The hydrodynamic radius (R<inf>h</inf>) was used to monitor changes in global structure. Circular dichroism spectroscopy showed that the GLY substitutions decreased polyproline II (PP<inf>II</inf>) propensities relative to the wild type, as expected, and fluorescence methods indicated that substitution-induced changes in R<inf>h</inf> were not associated with folding. The experiments showed that changes in local PP<inf>II</inf> structure cause changes in R<inf>h</inf> that are variable and that depend on the intrinsic chain propensities of PRO and ALA residues, demonstrating a mechanism for coupling local and global structure changes. Molecular simulations that model our results were used to extend the analysis to other proteins and illustrate the generality of the observed PRO and alanine effects on the structures of IDPs.

Original languageEnglish (US)
Pages (from-to)3373-3384
Number of pages12
JournalProteins: Structure, Function and Bioinformatics
Volume82
Issue number12
DOIs
StatePublished - 2014

Fingerprint

Proline
Alanine
Intrinsically Disordered Proteins
Proteins
Substitution reactions
Glycine
Circular dichroism spectroscopy
Molecular Models
Hydrodynamics
Circular Dichroism
Macromolecules
Signal Transduction
Spectrum Analysis
Theoretical Models
Fluorescence
Experiments

Keywords

  • Alanine
  • Hydrodynamic radius
  • Intrinsically disordered protein
  • Polyproline II
  • Proline

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins. / Perez, Romel B.; Tischer, Alexander; Auton, Matthew T; Whitten, Steven T.

In: Proteins: Structure, Function and Bioinformatics, Vol. 82, No. 12, 2014, p. 3373-3384.

Research output: Contribution to journalArticle

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