p97 complexes as signal integration hubs

See research article: http://www.biomedcentral.com/1741-7007/10/36 webciteThe ubiquitin-proteasome system mediates degradation of misfolded or damaged proteins to ensure cellular protein homeostasis, and selectively removes regulatory proteins in critical signaling pathways. The key step is the posttranslational modification of the substrate with the small protein ubiquitin and extension to ubiquitin chains that serve as a signal for degradation by the proteasome. The ubiquitylation reaction is mediated by a cascade of enzymes, comprising the E1 ubiquitin-activating enzyme, an E2 conjugating enzyme and an E3 ligase that functions in the attachment of the ubiquitin to the substrate (Figure 1). Ubiquitin-binding shuttling factors then deliver the ubiquitylated substrates to the proteasome. The conserved hexameric AAA+ ATPase p97 has emerged as an important player during this step for a subset of client proteins [1,2]. Unlike other shuttle proteins, which simply bind both to ubiquitin chains and to components of the proteasome, p97 uses the energy of ATP hydrolysis to structurally remodel or unfold its clients, and is believed thus to help extract them from cellular structures, segregate them from binding partners or generate initial unfolded stretches to facilitate degradation by the proteasome. This is required for degradation of proteins associated with the endoplasmic reticulum, with the outer mitochondrial membrane, and with chromatin, and for some soluble proteins [1,2]. The interaction of the p97 ATPase with the ubiquitylated substrate is mediated by diverse ubiquitin adapters [1,2], which recognize both p97 and the ubiquitin chain on its client protein. Members of the largest family of such adapters are characterized by UBX and UBX-like domains, which assume a ubiquitin-fold and bind the amino-terminal domain of p97 [3]. They also contain ubiquitin binding domains (UBDs), including the UBA domain, that recognize the client. The domain structures of p97 and its