Abstract
p62/SQSTM1 is the key autophagy adapter protein and the hub of multi-cellular signaling. It was recently reported that autophagy and N-end rule pathways are linked via p62. However, the exact recognition mode of degrading substrates and regulation of p62 in the autophagic pathway remain unknown. Here, we present the complex structures between the ZZ-domain of p62 and various type-1 and type-2 N-degrons. The binding mode employed in the interaction of the ZZ-domain with N-degrons differs from that employed by classic N-recognins. It was also determined that oligomerization via the PB1 domain can control functional affinity to the R-BiP substrate. Unexpectedly, we found that self-oligomerization and disassembly of p62 are pH-dependent. These findings broaden our understanding of the functional repertoire of the N-end rule pathway and provide an insight into the regulation of p62 during the autophagic pathway.
Highlights
P62/SQSTM1 is the key autophagy adapter protein and the hub of multi-cellular signaling
The autophagy adapter p62/SQSTM1/Sequestosome[1] was recently reported to recognize N-degrons, the N-end rule substrates of the well-characterized ubiquitin-proteasome system (UPS), and where these substrates are delivered to ALS8,9. p62 is a key selective autophagy adapter that plays a role in the degradation of various cellular constituents such as misfolded proteins and their aggregates, malfunctioning organelles, and invading pathogens[10,11,12,13]
P62 consists of six well-defined structural elements including Phox and Bem1p (PB1), ZZ-type zinc finger (ZZ), TRAF6binding (TB), LC3-interacting region (LIR), Keap1-interacting region (KIR), and ubiquitin-associated domain (UBA)[20] (Fig. 1a)
Summary
P62/SQSTM1 is the key autophagy adapter protein and the hub of multi-cellular signaling. It was recently reported that the central ZZ-domain in p62 plays a critical role in the recognition of N-terminal arginylated BiP/GRP78 by the Arg-tRNA transferase ATE1 (see ref.[8]) This domain is important for redirecting N-end rule substrates to the autophagy pathway. The Arg/N-end rule was the first characterized pathway and targets proteins with the following primary Nterminal residues: type-1 (Arg, Lys, and His; positively charged residues recognized by the UBR box) and type-2 (Phe, Tyr, Trp, Leu, and Ile; bulky hydrophobic residues recognized by the ClpShomology domain) N-degrons It is organized in hierarchical steps whereby tertiary destabilizing N-terminal Asn and Gln residues of N-end rule substrates are deamidated to secondary destabilizing Asp and Glu residues, and the Arg residue is subsequently attached to these destabilizing residues. The interplay between the PB1 and ZZ-domains has yet to be extensively investigated
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