Ligand-dependent dynamics and intramolecular signaling in a PDZ domain

Allosteric communication is a fundamental process that proteins use to propagate signals from one site to functionally important distal sites. Although allostery is usually associated with multimeric proteins and enzymes, "long-range" communication may be a fundamental property of proteins...

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Bibliographic Details
Published in:Journal of molecular biology 2004-01, Vol.335 (4), p.1105-1115
Main Authors: Fuentes, Ernesto J, Der, Channing J, Lee, Andrew L
Format: Article
Language:English
Subjects:
Allosteric Regulation
Amino Acid Motifs
Amino Acid Sequence
Animals
Binding Sites
Humans
Ligands
Mice
Models, Molecular
Molecular Sequence Data
Peptides - chemistry
Peptides - metabolism
Protein Binding
Protein Structure, Tertiary
Protein Tyrosine Phosphatases - chemistry
Protein Tyrosine Phosphatases - metabolism
Signal Transduction
Thermodynamics
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Summary:Allosteric communication is a fundamental process that proteins use to propagate signals from one site to functionally important distal sites. Although allostery is usually associated with multimeric proteins and enzymes, "long-range" communication may be a fundamental property of proteins. In some cases, communication occurs with minimal structural change. PDZ (post-synaptic density-95/discs large/zonula occludens-1) domains are small, protein-protein binding modules that can use multiple surfaces for docking diverse molecules. Furthermore, these domains have long-range energetic couplings that link the ligand-binding site to distal regions of the structure. Here, we show that allosteric behavior in a representative member of the PDZ domain family may be directly detected using side-chain methyl dynamics measurements. The changes in side-chain dynamics parameters in the second PDZ domain from the human tyrosine phosphatase 1E (hPTP1E) were determined upon binding a peptide target. Long-range dynamic effects were detected that correspond to previously observed pair-wise energetic couplings. These results provide one of the first experimental examples for the potential role of ps-ns timescale dynamics in propagating long-range signals within a protein, and reinforce the idea that dynamic fluctuations in proteins contribute to allosteric signal transduction.
ISSN:0022-2836
DOI:10.1016/j.jmb.2003.11.010