Designing ۲۶S Proteasome Activating Peptides

Background and Aim: The ۲۶S proteasomes maintain protein homeostasis through the degradation of damaged proteins which are tagged by polyubiquitination. Therefore, enhancing proteasome activity has been identified as a novel method to protect against proteotoxic diseases. USP۱۴ is a subunit of the ۲۶S proteasome, which can rescue substrates from degradation by the elimination of the ubiquitin. Thus, the design of an inhibitor for USP۱۴ could enhance protein degradation. USP۱۴ includes a UBL domain, which is a critical regulator of proteasomal activity. Recently it has been demonstrated that the UBL domain stimulates the degradation of peptides, non-ubiquitinated, and ubiquitinated proteins. Considering the importance of the functional UBL domain, structural investigation of USP۱۴ interaction with the proteasome would be helpful in drug design.Methods: In order to design proteasome activating peptides, first, the interaction of the UBL domain of USP۱۴ (PDB ID: ۱WGG) and Rpn۱ subunit of the proteasome (PDB ID: ۴CR۲) was investigated using HADDOCK ۲.۲. Then, a core peptide inhibitor was designed using PeptiDerive from the Rosetta package, and a library of peptides was created based on the interaction pattern. Finally, the binding energy of each peptide with the binding site was calculated using Autodock software.Results: Based on the docking results, the core peptide has the binding energy of -۴.۴۵ kcal/mol and the binding energy ranges for the peptide library were from -۵.۳۶ to ۱.۱۲ kcal/mol. Therefore, among ten amino acid sequences in the peptide library, SQPARQK, with binding energy of -۵.۳۶ kal/mol was selected as a suitable peptide to inhibit USP۱۴ activity because of its high binding affinity relative to the core peptide.Conclusion: According to these studies, the proposed peptide may be able to prevent the binding of USP۱۴ to the proteasome by inhibiting its effective interaction at the RPN۱ site, and therefore increasing the activity of the proteasome.

Keywords:

۲۶S proteasome , USP۱۴ , UBL , activating peptides