Intrinsically disordered proteins (IDPs) are a prominent class of low abundance and short-lived signaling molecules. IDPs are unique in that they contain regions that do not adopt a defined three-dimensional structure. The disordered conformation allows the IDP to interact with multiple protein partners and control multiple cellular events. Dysfunctional cell signaling can lead to accumulation of IDPs such as alpha-synuclein, tau, ornithine decarboxylase and p21, resulting in harmful signaling events directly associated with the pathogenesis of multiple neurodegenerative diseases and cancers. In contrast to ubiquitinated proteins, which are degraded by the 26S proteasome, IDPs are directly targeted by the 20S proteasome for rapid degradation. Here, we show by atomic force microscopy (AFM) that the imidazoline, TCH-165, induces an open-gate conformation of the human 20S proteasome <i>in vitro</i>. This active conformation showed enhanced degradation of peptide substrates, alpha-synuclein and tau in purified protein assay.  In cells, TCH-165 inhibits the formation of a double capped 26S proteasome and generates proteolytically active 20S and single capped 20S proteasome hybrids. These proteasome hybrids enhance the degradation of IDPs, while preventing the accumulation of ubiquitinated proteins. At higher concentrations of TCH-165, the 26S proteasome fully disassembles into its 19S and 20S particles, resulting in enhanced IDP degradation and modest accumulation of ubiquitinated proteins. These findings provide support for the therapeutic potential of small molecule modulator of 20S/26S dynamic equilibrium, to increase the clearance of oncogenic IDPs associated with a number of cancers.<br/>

Small molecule modulator of 20S/26S proteasome dynamic equilibrium targets intrinsically disordered proteins

256th National Meeting (2018)

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