Abstract
PA28 (also known as 11S, REG or PSME) is a family of proteasome regulators whose members are widely present in many of the eukaryotic supergroups. In jawed vertebrates they are represented by three paralogs, PA28α, PA28β, and PA28γ, which assemble as heptameric hetero (PA28αβ) or homo (PA28γ) rings on one or both extremities of the 20S proteasome cylindrical structure. While they share high sequence and structural similarities, the three isoforms significantly differ in terms of their biochemical and biological properties. In fact, PA28α and PA28β seem to have appeared more recently and to have evolved very rapidly to perform new functions that are specifically aimed at optimizing the process of MHC class I antigen presentation. In line with this, PA28αβ favors release of peptide products by proteasomes and is particularly suited to support adaptive immune responses without, however, affecting hydrolysis rates of protein substrates. On the contrary, PA28γ seems to be a slow-evolving gene that is most similar to the common ancestor of the PA28 activators family, and very likely retains its original functions. Notably, PA28γ has a prevalent nuclear localization and is involved in the regulation of several essential cellular processes including cell growth and proliferation, apoptosis, chromatin structure and organization, and response to DNA damage. In striking contrast with the activity of PA28αβ, most of these diverse biological functions of PA28γ seem to depend on its ability to markedly enhance degradation rates of regulatory protein by 20S proteasome. The present review will focus on the molecular mechanisms and biochemical properties of PA28γ, which are likely to account for its various and complex biological functions and highlight the common features with the PA28αβ paralog.
Highlights
(PA28αβ) or homo (PA28γ) rings on one or both extremities of the 20S proteasome cylindrical structure
It is generally believed that other specific characteristic, yet to be identified, in tridimensional structures and/or chemical-physical properties are responsible for their susceptibility to PA28γ-enhanced degradation [157]
By assessing the rates of in vitro hydrolysis by the 20S proteasome of several naturally or chemically unfolded proteins, we recently demonstrated that PA28γ strongly accelerates the proteasomal degradation of all unstructured proteins tested, while it is completely inactive toward their native, folded counterparts [61]
Summary
Homolog-specific inserts, and and actiactivation loop displayed. Structure of the het- PA28αβ (left) and homoheptameric (right). One α (blue), one β (green) and one γ (magenta) subunit areand highlighted. Eroheptameric PA28αβ (left) and homoheptameric PA28γ (right). Structures were generated by ChimeraX using the PA28αβ one γ (magenta) subunit are highlighted. Struc- crystal tures were generated by ChimeraX using One the PA28αβ crystal (B) of Structure. Α (blue) and onestructure β (green) [45]. One α Structures (blue) andwere one βgenerated (green) subunit of PA28 and the α1 (red) and β1 (yellow). Structures were generated by ChimeraX using the 20S-PA28αβ EM structure [51]
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