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Conformational Plasticity in dsRNA-Binding Domains Drives Functional Divergence in RNA Recognition
Debadutta Patra1,2, Jaydeep Paul1,2, Upasana Rai1,2
1CSIR─Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
Journal of the American Chemical Society
|May 6, 2025
Summary
Protein structural dynamics, not just sequence, dictate function. This study reveals how protein flexibility in dsRNA-binding domains (dsRBDs) drives functional differences in substrate recognition, impacting biological outcomes.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biophysics
Background:
- Protein functional specificity is often linked to sequence and structure, overlooking conformational dynamics.
- Understanding protein dynamics is crucial for deciphering biological mechanisms and disease.
- Double-stranded RNA-binding domains (dsRBDs) are key regulators of RNA biology.
Purpose of the Study:
- To investigate the role of conformational dynamics in the functional divergence of dsRNA-binding domain (dsRBD) paralogs.
- To elucidate the differential substrate recognition mechanisms of DRB2D1 and DRB3D1.
- To explore how intrinsic protein dynamics govern specificity in dsRBD:dsRNA interactions.
Main Methods:
- Utilized 15N-CEST NMR spectroscopy to probe protein dynamics.
- Employed RDC-corrected metainference molecular dynamics simulations.
- Combined experimental and computational approaches to capture conformational ensembles.
Main Results:
- DRB3D1 exhibits structural plasticity enabling recognition of flexible dsRNA, unlike the rigid DRB2D1.
- Identified differential substrate recognition mechanisms between dsRBD paralogs.
- Captured intermediate protein conformations, providing a more complete picture beyond ground and excited states.
Conclusions:
- Intrinsic structural dynamics play a pivotal role in driving functional divergence between protein paralogs.
- Protein flexibility is a key determinant of specificity in dsRBD:dsRNA interactions.
- A multi-timescale dynamics approach reveals nuanced mechanisms of molecular recognition.
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