Change in allosteric network affects binding affinities of PDZ domains: analysis through perturbation response scanning

PLoS Comput Biol. 2011 Oct;7(10):e1002154. doi: 10.1371/journal.pcbi.1002154. Epub 2011 Oct 6.

Abstract

The allosteric mechanism plays a key role in cellular functions of several PDZ domain proteins (PDZs) and is directly linked to pharmaceutical applications; however, it is a challenge to elaborate the nature and extent of these allosteric interactions. One solution to this problem is to explore the dynamics of PDZs, which may provide insights about how intramolecular communication occurs within a single domain. Here, we develop an advancement of perturbation response scanning (PRS) that couples elastic network models with linear response theory (LRT) to predict key residues in allosteric transitions of the two most studied PDZs (PSD-95 PDZ3 domain and hPTP1E PDZ2 domain). With PRS, we first identify the residues that give the highest mean square fluctuation response upon perturbing the binding sites. Strikingly, we observe that the residues with the highest mean square fluctuation response agree with experimentally determined residues involved in allosteric transitions. Second, we construct the allosteric pathways by linking the residues giving the same directional response upon perturbation of the binding sites. The predicted intramolecular communication pathways reveal that PSD-95 and hPTP1E have different pathways through the dynamic coupling of different residue pairs. Moreover, our analysis provides a molecular understanding of experimentally observed hidden allostery of PSD-95. We show that removing the distal third alpha helix from the binding site alters the allosteric pathway and decreases the binding affinity. Overall, these results indicate that (i) dynamics plays a key role in allosteric regulations of PDZs, (ii) the local changes in the residue interactions can lead to significant changes in the dynamics of allosteric regulations, and (iii) this might be the mechanism that each PDZ uses to tailor their binding specificities regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Allosteric Regulation / physiology
  • Amino Acid Sequence
  • Computational Biology
  • Humans
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • PDZ Domains / genetics
  • PDZ Domains / physiology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism
  • Signal Transduction

Substances

  • PTPN13 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13