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Abstract
p62/SQSTM1/A170 is a multimodular protein that is found in ubiquitin-positive inclusions associated with neurodegenerative diseases. Recent findings indicate that p62 mediates the interaction between ubiquitinated proteins and autophagosomes, leading these proteins to be degraded via the autophagy-lysosomal pathway. This ubiquitin-mediated selective autophagy is thought to begin with recognition of the ubiquitinated proteins by the C-terminal ubiquitin-associated (UBA) domain of p62. We present here the crystal structure of the UBA domain of mouse p62 and the solution structure of its ubiquitin-bound form. The p62 UBA domain adopts a novel dimeric structure in crystals, which is distinctive from those of other UBA domains. NMR analyses reveal that in solution the domain exists in equilibrium between the dimer and monomer forms, and binding ubiquitin shifts the equilibrium toward the monomer to form a 1:1 complex between the UBA domain and ubiquitin. The dimer-to-monomer transition is associated with a structural change of the very C-terminal end of the p62 UBA domain, although the UBA fold itself is essentially maintained. Our data illustrate that dimerization and ubiquitin binding of the p62 UBA domain are incompatible with each other. These observations reveal an autoinhibitory mechanism in the p62 UBA domain and suggest that autoinhibition plays a role in the function of p62.
Highlights
Impairment of the ubiquitin-proteasome system is one of major causes of ubiquitin-positive inclusions found in various neurodegenerative diseases [1]
A likely scenario of ubiquitin-mediated “selective autophagy” includes the following: p62 interacts with ubiquitinated proteins, leading to the formation of protein aggregates that are recruited to autophagosomes via interaction with LC3, a mammalian homo
Truncation of the tail dramatically enhances the apparent affinity of the p62 UBA domain for ubiquitin, presumably because of the absence of the monomer-dimer equilibrium that competes with ubiquitin binding
Summary
Impairment of the ubiquitin-proteasome system is one of major causes of ubiquitin-positive inclusions found in various neurodegenerative diseases [1]. Recent studies have identified the involvement of another degradation system, the autophagy-lysosomal pathway, in the formation of ubiquitin-positive inclusions as exemplified by the observation that autophagy-deficient mice exhibit substantial accumulation of such inclusions in tissues [2]. Accumulating evidence indicates that p62 is a receptor for ubiquitinated proteins that are targeted to the autophagosome for lysosomal degradation. It is involved in autophagic elimination of damaged mitochondria, midbody rings, peroxisomes, and microbes (6 –10). A similar result was reported in fruit flies [12] These observations indicate that p62 is critically involved in the development of ubiquitin-positive inclusions that should be degraded via autophagy. The existence of the monomer-dimer equilibrium may provide a regulatory process for the p62/ubiquitin interaction
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