Misfolded PrP and a novel mechanism of proteasome inhibition

Abstract

Prion diseases comprise a family of fatal neurodegenerative disorders caused by the conformational re-arrangement of a normal host-encoded protein, PrP (C) , to an abnormal infectious isoform termed PrP (Sc) . Currently, the precise cellular mechanism(s) underlying prion disease pathogenesis remain unclear. Evidence suggests a role for the ubiquitin proteasome system (UPS), a protein degradation pathway that is critical for maintaining cellular proteostasis. Dysfunction of the UPS has been implicated in various neurodegenerative diseases. However, the mechanisms of this impairment remain unknown in many cases, and evidence that disease-associated misfolded proteins are able to directly inhibit the function of the proteasome has been lacking. Recently, we have shown data describing a mechanism of proteasome impairment by the direct interaction of β-sheet-rich PrP to reduce gate opening and inhibit substrate entry. This novel mechanism may provide a model for how other misfolded, disease-associated proteins might interact with the proteasome to disrupt its function. Targeting the UPS to restore proteostasis in neurodegenerative disorders in which misfolded proteins accumulate offers a possible target for therapeutic intervention.

Figure 1

The 20S proteasome comprises four rings of seven subunits each. The two inner rings each contain seven β-subunits, including the β₁, β₂ and β₅ sites that exhibit caspase-like, trypsin-like and chymotrypsin-like activities respectively. The two outer rings each contain seven α-subunits, the N-termini of which form the gate that prevents substrate entry in its closed state, but when open allows substrate entry through the translocation pore into the catalytic core. The 19S ATPases dock into the intersubunit pockets of the α-ring to cause gate opening. Similarly, 11S activators, such as the PA26 shown here, also bind to the α-ring intersubunit pockets, but cause gate opening by an alternative mechanism. The finding that aggregated β-sheet-rich PrP and PA26 do not bind to the same part of the 20S proteasome illustrates that such PrP species cause their antagonistic effect on gate opening by binding to the proteasome's lateral surface. Figure adapted from Deriziotis P, et al. EMBO J 2011; 30:3065–77, courtesy of David M. Smith, West Virginia University School of Medicine.