Abstract
The ATP-powered protein degradation machinery plays essential roles in maintaining protein homeostasis in all organisms. Robust proteolytic activities are typically sequestered within protein complexes to avoid the fatal removal of essential proteins. Because the openings of proteolytic chambers are narrow, substrate proteins must undergo unfolding. AAA superfamily proteins (ATPases associated with diverse cellular activities) are mostly located at these openings and regulate protein degradation appropriately. The 26S proteasome, comprising 20S peptidase and 19S regulatory particles, is the major ATP-powered protein degradation machinery in eukaryotes. The 19S particles are composed of six AAA proteins and 13 regulatory proteins, and bind to both ends of a barrel-shaped proteolytic chamber formed by the 20S peptidase. Several recent studies have reported that another AAA protein, Cdc48, can replace the 19S particles to form an alternative ATP-powered proteasomal complex, i.e., the Cdc48-20S proteasome. This review focuses on our current knowledge of this alternative proteasome and its possible linkage to amyotrophic lateral sclerosis.
Highlights
Specialty section: This article was submitted to Protein Folding, Misfolding and Degradation, a section of the journal Frontiers in Molecular Biosciences
This review focuses on our current knowledge of this alternative proteasome and its possible linkage to amyotrophic lateral sclerosis
The 26S proteasome is composed of a 20S core peptidase, which is called as the 20S proteasome, and 19S regulatory particles (RP) (Figure 1A; for review, see Baumeister et al, 1998; Finley, 2009; Tanaka, 2009; Finley et al, 2016)
Summary
The AAA protein Cdc, known as p97, VCP, and TER94, is one of the most abundant intracellular proteins and is highly conserved in all eukaryotic species. A threading mechanism has been proposed as a common molecular mechanism for several AAA hexameric rings including the Rpt subunits of 19S RP (Ogura et al, 2008) In this mechanism, substrate proteins pass through the narrow central pore of AAA domains in an ATP-dependent manner, resulting in the unfolding of substrate proteins. The typical threading mechanism-driven unfolding reaction requires a loop structure protruding into the central pore of the AAA domains (pore loop) with a conserved XG (aromatic, any, and glycine residues) sequence motif. Cdc mutants with an essential XG sequence motif in the first AAA domain acquired robust unfolding activity in vitro the N-terminal regulatory domain must be removed concomitantly (Rothballer et al, 2007). Sod is known to be one of the most stable proteins (Rakhit and Chakrabartty, 2006), which suggests that Sod is an endogenous substrate of the Cdc48-20S proteasome (Esaki et al, 2017)
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