“Like a sticky sugar muffin that gets stucked in its paper wrap, ubiquitin-tagged misfolded protein aggregates are tightly attached to LC3-positive isolation membranes via p62 during selective autophagy in human cells.”
In their work published in 2015 in eLife, B. Wurzer, G. Zaffagnini and colleagues from the lab of Professor Sascha Martens at the Max Perutz Labs (Vienna, AT) biochemically characterize the autophagy receptor molecule p62/SQSTM1, a key player in human aggrephagy.
p62 (violet rods) was already known for its ability to simultaneously bind ubiquitin (orange), a tag on misfolded protein aggregates (light blue), and LC3 (dark violet globular) molecules, a hallmark of autophagic membranes (in yellow), employing two distinct domains: the UBA (UBiquitin-Associated) and the LIR (LC3 Interacting Region), respectively. In their work, B. Wurzer, G. Zaffagnini and colleagues disclose the significance of another p62 domain, known as the PB1 (Phox and Bem1) domain. It mediates the self-interaction between p62 molecules resulting in their oligomerization, that is the ability to form complexes of a high number of monomers. Within these complexes, when p62 binds ubiquitinated cargoes and LC3 moieties, the avidity between these interactors increases and results in the tight coupling of cargoes to autophagic membranes. The authors present this as a strategic mechanism at the basis of an efficient removal of misfolded protein aggregates and intracellular pathogens’ employed by mammalian cells during aggrephagy and xenophagy, respectively.
Read the full research article here: https://elifesciences.org/articles/08941