Loop dynamics govern MALT1 activation revealed by integrative AlphaFold, MD, and NMR analysis

Area of Science:

• Molecular Biology
• Structural Biology
• Immunology

Background:

• Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for immune signaling pathways.
• The precise conformational dynamics governing MALT1 activation remain largely uncharacterized.

Purpose of the Study:

• To investigate the solution-state dynamics of the MALT1 catalytic core (MALT1(PCASP-Ig3)_339-719).
• To understand how varying ionic conditions affect MALT1 conformational equilibria and activity.

Main Methods:

• Integration of NMR relaxation measurements, molecular dynamics simulations, and ensemble modeling.
• Characterization of MALT1 dynamics under low, intermediate, and high salt concentrations.

Main Results:

• Low salt conditions favor a dominant inactive MALT1 ensemble, driven by specific residue rotations and loop rearrangements.
• Intermediate salt allows transient access to active-like states via reversible loop motions.
• High salt conditions restrict loop dynamics, stabilizing the protein in its initial conformation.

Conclusions:

• Ionic strength is a critical determinant of MALT1 conformational dynamics and equilibria in solution.
• Coordinated loop dynamics regulate access to catalytically active MALT1 states.
• Findings provide a dynamic framework for structure-based MALT1 modulation.