CHIP: A Co-chaperone for Degradation by the Proteasome - The Networking of Chaperones by Co-chaperones - page 219

Fig. 11.2 Degradation of proteins via the ubiquitin-proteasome system. Conjugation of polyu-
biquitin chains to substrate proteins is catalysed as part of an ATP dependent enzyme catalysed
cascade that precedes protein recognition and degradation by the proteasome. ( 1 ) The process is
initiated by the activation of ubiquitin via conjugation to an ubiquitin activating enzyme (E1) via
a thioester bond. ( 2 ) The ubiquitin moiety is subsequently transferred to ubiquitin conjugating
enzyme (E2), which ( 3 ) subsequently forms a complex with a specific ubiquitin ligase (E3) and a
substrate protein. ( 4 ) The E3 ligase transfers the ubiquitin to lysine residues within the substrate
protein. This cycle is repeated multiple times to generate substrate proteins linked to polyubiquitin
chains. ( 5 ) Polyubiquitination, particularly via K48 linkages, is the signal for transfer of substrate
proteins to the proteasome. ( 6 ) At the proteasome, ubiquitinated substrates interact with the 19S
regulatory particle which deubiquitinates them and passes them into the central cavity of the core
20S proteasome. Here in the active site, proteins are degraded and peptides released. Ubiquitin
molecules can subsequently be recycled. 19S: regulatory particle, 20S: core particle
by members of the Ubc4, Ubc5 and Ubc7 E2 ubiquitin conjugating enzymes.
In contrast, K63 ubiquitination may have a regulatory function (Jacobson et al.
2009 ) and is catalysed by the Ubc13 E2 in complex with other Ubc proteins
(e.g. Uev1a) (Hofmann and Pickart 1999 ; Sun and Chen 2004 ). Most often, the
selectivity of protein degradation is controlled by the E3 ligase. These E3 ligases
integrate with the cellular molecular chaperone system, which is used as the
recognition system of the misfolded substrate during this process. In this way,
the numerous different E3 isoforms, each of which may be specific for certain
protein substrates, are able to utilise the innate ability of chaperones to cap-
ture a range of misfolded substrates, to target specific proteins for degradation
(Kriegenburg et al. 2012 ; Esser et al. 2004 ).