Friday, May 23, 2025
5/23/2025
Function and Pathway outcomes of Dynamic Protein Structures - PROJECT SUMMARY Protein structure and dynamics are key parameters for determining the function of proteins as enzymes, binding partners, and key players in cellular signaling pathways and responses including protein quality control and antibiotic resistance. Binding events, catalysis, and posttranslational modifications can each effect changes in structure and dynamics to yield positive or negative regulation of protein activity and downstream function in relevant cellular pathways. Cellular protein quality control systems enable the robust response to protein misfolding that is essential for normal cellular function. Numerous pathologies including neurodegenerative disorders, ataxias, and cancers can result from defects in the protein quality control system formed by the interaction of the E3 ubiquitin ligase CHIP (C-terminus of Hsp70 Interacting Protein) and the ATP-dependent chaperone Hsp70 (70 kilodalton heat shock protein). Despite the importance of the CHIP/Hsp70 protein quality control complex, the dynamics and structures that enable the triage mechanism used by the CHIP/Hsp70 complex to target misfolded proteins for either Hsp70-mediated refolding or ubiquitin proteasome-mediated degradation are unknown. Antibiotic resistance mediated by beta-lactamases enables bacteria to evade treatment. While it is clear that dynamic changes occur within the structure of beta-lactamases, the detailed molecular mechanism for how these dynamics dictate the activity of the beta-lactamase toward front-line antibiotics is not well understood. How to exploit these dynamics to enable selective and potent inhibition is also not understood. Across this diverse set of proteins, biological posttranslational modifications (PTMs) and synthetic PTMs provide opportunities to further modulate activity. Within the protein quality control pathway, biological PTMs are most commonly observed through phosphorylation and methylation. A greater understanding of how PTMs alter structure and dynamics of CHIP and Hsp70 are greatly needed, particularly given the critical role of dynamics in enabling CHIP-mediated ubiquitination of Hsp70-bound clients. Synthetic PTMs for beta-lactamases are most commonly encountered for drugs that covalently modify the protein and fundamental knowledge of how these modifications alter the dynamics of the beta-lactamase is not available. Across the protein quality control and antibiotic resistance projects, the rational design of potent and specific drugs requires a greater understanding of the structures and dynamics that regulate each process and pathway. Existing gaps in our knowledge of the extent and role of dynamics prevent each field from utilizing rational design to produce new therapeutics.
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