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Sequence-specific long range networks in PSD-95/discs large/ZO-1 (PDZ) domains tune their binding selectivity
Stefano Gianni1, S Raza Haq, Linda C Montemiglio
1Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche A. Rossi Fanelli, Sapienza Università di Roma, Piazzale A. Moro 5, 00185 Rome, Italy.
The Journal of Biological Chemistry
|June 10, 2011
Summary
Researchers identified functional energetic networks in PDZ domains, revealing how specific protein-protein interactions are fine-tuned. This allosteric mechanism involves remote residues, optimizing the entire domain for ligand selectivity.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Protein-protein interactions are essential for cellular functions.
- Modular protein domains mediate these interactions, but achieving specificity among many ligands is challenging.
- Intradomain allostery, where remote residues influence binding sites, is a proposed mechanism for specificity.
Purpose of the Study:
- To experimentally validate and characterize functional energetic networks mediating intradomain allostery in PDZ domains.
- To investigate the role of these networks in fine-tuning protein-ligand recognition and selectivity.
Main Methods:
- Utilized double mutant cycles with site-directed mutagenesis on both PDZ domains and peptide ligands.
- Employed kinetic analyses to determine the energetic details of interaction networks.
- Analyzed two homologous PDZ-ligand complexes.
Main Results:
- Identified functional energetic networks within PDZ domains that contribute to peptide recognition.
- Demonstrated that specific energetically coupled residues differ between homologous PDZ-ligand complexes.
- Found that amino acid sequence, not just domain topology, dictates allosteric pathways.
Conclusions:
- Experimental evidence supports the existence and functional role of intradomain allosteric networks in PDZ domains.
- Allosteric pathways are dictated by specific amino acid sequences, allowing for fine-tuning of ligand selectivity.
- The entire protein domain, not just the binding pocket, is optimized for specific ligand interactions.
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