Sequestosome-1 ZZ domain (p62 ZZ domain)

The Sequestosome-1 ZZ domain (p62 ZZ domain) is a zinc finger domain within the Sequestosome-1 (SQSTM1/p62) protein that specifically recognizes and binds type-1 and type-2 N-degrons, including N-terminal arginine (Nt-Arg), as part of the N-end rule pathway for targeted protein degradation. This domain is structurally and functionally homologous to the UBR box of classic N-recognins, but employs a distinct binding mode for substrate recognition. The p62 ZZ domain is essential for the aggregation of p62 and its cargo, facilitating their delivery to autophagosomes for lysosomal degradation, a process critical for cellular homeostasis and stress response. It also contributes to the regulation of mTORC1 signaling and may modulate p62's own function through intramolecular interactions with a regulatory linker sequence. Mutations in the ZZ domain and its neighboring regions have been implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis, highlighting its importance in protein quality control and cellular health. The domain acts as a multiprotein and RNA interaction hub, linking the ubiquitin-proteasome system with selective autophagy pathways.

Other names

SQSTM1 ZZ domainp62/SQSTM1 ZZ domainN-recognin homologous to UBR box