James R. Cavey

TL;DR: Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain, and functional and structural analysis showed that disease severity was related to the type of mutation but was unrelated to the polyubiquitin‐binding properties of the mutant UBAdomain peptides.

TL;DR: The p62 protein functions as a scaffold in signaling pathways that lead to activation of NF-κB and is an important regulator of osteoclastogenesis, and the structural basis for ubiquitin recognition by the UBA domain of p62 has been investigated using NMR and reveals a novel binding mechanism involving a slow exchange structural reorganization.

TL;DR: The first NMR structure of a recombinant polypeptide that contains the C-terminal UBA domain of the human p62 protein is reported, which forms a compact three-helix bundle with a structure analogous to the UBA domains of HHR23A but with differences in the loop regions connecting helices that may be involved in binding accessory proteins.

TL;DR: It is shown that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B, a key protein-protein interaction in autophagy which could expose a vulnerability over the lifetime of a neuron, which ultimately tips the balance from cell survival toward cell death.

TL;DR: Non-ubiquitylated forms of the principal ubiquitylated components of Alzheimer's disease neurofibrillary tangles and Parkinson's disease Lewy bodies, tau and alpha-synuclein proteins, respectively, can be degraded by proteasomes in a pathway which does not have an absolute requirement for ubiquitylation.