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Decoding the deactivation mechanism of R192W mutation of ZAP-70 using molecular dynamics simulations and binding free
Xuehua Zhang1, Wenqi Liang2, Guodong Zheng3
1Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China.
Context:
ZAP-70 (zeta-chain-associated protein of 70 kDa), serving as a critical regulator for T cell antigen receptor signaling, represents an attractive therapeutic target for autoimmunity disease. How the mechanistical mechanism of ZAP-70 to a human autoimmune syndrome-associated R192W mutation remains unclear. The results indicated that the R192W mutation of ZAP-70 clearly affected the conformational flexibility of the N-terminal ITAM-Y2P. Structural analysis unveiled that the R192W mutation of ZAP-70 caused the exposure of the N-terminal ITAM-Y2P to the solvent. MM-GBSA binding free energy calculations exhibited that the R192W mutation decreased the binding affinity of ITAM-Y2P to the ZAP-70 mutant. Residue-based free energy decomposition further revealed that the protein-peptide interaction networks involving electrostatic interactions provide significant contributions for complex formation. The energy unfavorable residues include Arg43, Arg192, Tyr240, and Lys244 from ZAP-70 and Asn301, Leu303, pY304, and pY315 from ITAM-Y2P in the R192W mutant. Our obtained results may help the understanding of the deactivation mechanism of ZAP-70 induced by the R192W mutation.
Methods:
In the work, multiple replica molecular dynamics simulations and molecular mechanics-generalized Born surface area (MM-GBSA) method were performed to reveal the doubly phosphorylated ITAMs (ITAM-Y2P)-mediated deactivation mechanism of ZAP-70 induced by the R192W mutation.
Insights
The R192W mutation in ZAP-70 (zeta-chain-associated protein of 70 kDa) disrupts T cell signaling by altering protein structure and reducing binding affinity. This study clarifies the deactivation mechanism of ZAP-70 in autoimmune diseases.
Area of Science:
- Molecular Biology
- Immunology
- Computational Biophysics
Background:
- ZAP-70 (zeta-chain-associated protein of 70 kDa) is crucial for T cell receptor signaling and a therapeutic target for autoimmune diseases.
- The R192W mutation's impact on ZAP-70's mechanism in autoimmune syndromes is not well understood.
Purpose of the Study:
- To elucidate the deactivation mechanism of ZAP-70 caused by the R192W mutation.
- To investigate the structural and energetic consequences of the R192W mutation on ZAP-70 function.
Main Methods:
- Multiple replica molecular dynamics simulations.
- Molecular mechanics-generalized Born surface area (MM-GBSA) calculations.
- Residue-based free energy decomposition analysis.
Main Results:
- The R192W mutation alters ZAP-70's conformational flexibility, exposing the N-terminal ITAM-Y2P region.
- Binding affinity between ITAM-Y2P and ZAP-70 is reduced by the R192W mutation.
- Electrostatic interactions are key in complex formation, with specific residues identified as unfavorable in the mutant.
Conclusions:
- The R192W mutation deactivates ZAP-70 by affecting ITAM-Y2P binding and conformational stability.
- Findings provide insights into the molecular basis of ZAP-70 dysfunction in certain autoimmune conditions.
- Understanding this mechanism may inform therapeutic strategies for autoimmune diseases targeting ZAP-70.
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