Regulation of Ubiquitin Independent Proteasomal Degradation of Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) are labile proteins and undergo degradation by ubiquitin dependent and independent mechanisms. Previously we reported on the 20S proteasomal degradation pathway of the IDPs that is regulated by NQO1, a 20S associated protein, and by Nannies. Nannies are IDP interacting proteins functioning to inhibit IDPs proteasomal degradation. However the question of whether and how the IDPs are targeted to the 20S proteasome remained open. To address this question, we adopted the BiFC cell based technique for visualizing protein interactions with 20S proteasome. We found that IDPs interact with a subset of 20S proteasome alpha subunits. The results suggest that the 20S proteasome has two hub sites for interaction with IDPs in the alpha ring. We focused on the subunit PSMA3 and showed that its C terminus interacts with multiple IDPs. Thus, it implies that IDPs are targeted to the 20S proteasome prior to their degradation. In addition, lately we have identified a new type of 26S proteasomes whereby no ATP but NADH regulates its assembly. We have evidence for this new type of NADH‐26S proteasomes preferentially involved in IDPs degradation. Finally we will report on a new proteomic approach in identifying the selective 20S proteasomes substrates.Asher, G., Reuven, N. and Shaul, Y. (2006). 20S proteasomes and protein degradation by default. BioEssay. 28(8):844‐849.Tsvetkov, P., Reuven, N. and Shaul Y. (2009). The nanny model for IDPs. Nat Chem Biol. 5(11):778‐81Tsvetkov P, Myers N, Eliav R, Adamovich Y, Hagai T, Adler J, Navon A, and Shaul Y. (2014). NADH Binds and Stabilizes the 26S Proteasomes Independent of ATP. J Biol Chem. Apr 18;289(16):11272‐81.