Conformational selection and linker-dependent specificity in the MAGI-1 WW tandem.
Julian Toso1, Eduarda Santos Ventura1, Valeria Pennacchietti1
1Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma - Laboratory affiliated to Istituto Pasteur Italy - Fondazione Cenci Bolognetti, 00185, Rome, Italy.
The MAGI-1 WW tandem scaffold enhances protein binding affinity and specificity by stabilizing complexes and utilizing conformational selection. Its structure, sensitive to linker length and pH, enables precise regulation of protein interactions.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Scaffold proteins utilize tandem domains for enhanced affinity and specificity.
- The MAGI-1 scaffold's WW tandem domain's role in ligand recognition was previously unclear.
Purpose of the Study:
- To investigate the mechanistic contribution of the MAGI-1 WW tandem to ligand recognition.
- To understand how tandem architecture influences binding affinity and specificity.
Main Methods:
- Time-resolved kinetic analyses.
- Calorimetric measurements.
- Investigation of pH modulation and inter-motif spacing effects.
Main Results:
- The MAGI-1 WW tandem significantly enhances affinity for bidentate ligands by stabilizing the complex.
- Binding occurs via conformational selection, with the tandem sampling states before engagement.
- Ligand recognition is sensitive to linker length and pH, affecting complex stability.
Conclusions:
- The MAGI-1 WW tandem functions as a dynamic supradomain, overcoming promiscuity of single WW modules.
- Geometric and conformational signals integrated by the tandem enable selective regulation of protein-protein interaction networks.
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