A5055697856- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Bone health and treatments
- Autophagy in Disease and Therapy
- Cancer, Hypoxia, and Metabolism
- RNA Research and Splicing
- NF-κB Signaling Pathways
- Amyotrophic Lateral Sclerosis Research
- Cell death mechanisms and regulation
- interferon and immune responses
- Genetics and Neurodevelopmental Disorders
- Biochemical and Molecular Research
- DNA Repair Mechanisms
- Neurogenetic and Muscular Disorders Research
- Toxoplasma gondii Research Studies
- Cytokine Signaling Pathways and Interactions
- Genetic Neurodegenerative Diseases
- Click Chemistry and Applications
- Alzheimer's disease research and treatments
- Bacterial Genetics and Biotechnology
- Parkinson's Disease Mechanisms and Treatments
- RNA modifications and cancer
- PARP inhibition in cancer therapy
- Cancer therapeutics and mechanisms
University of Nottingham
2007-2023
Queen's Medical Centre
2003-2011
The p62 protein functions as a scaffold in signaling pathways that lead to activation of NF-kappaB and is an important regulator osteoclastogenesis. Mutations affecting the receptor activator axis can result human skeletal disorders, including those identified C-terminal ubiquitin-associated (UBA) domain patients with Paget disease bone. These observations suggest may involve common mechanism related alterations ubiquitin-binding properties p62. structural basis for ubiquitin recognition by...
Growing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, encodes receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects disease-associated variants have not been described. A key protein-protein interaction recognition lipid-anchored form LC3 (LC3-II)...
Abstract Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain. Functional and structural analysis showed that disease severity was related to type mutation but unrelated polyubiquitin-binding properties mutant domain peptides. Introduction: Mutations ubiquitin-associated (UBA) Sequestosome 1 (SQSTM1) gene have recently been as a common cause Paget's bone (PDB), mechanisms responsible are unclear. We three conducted functional analyses...
The p62 protein (also known as SQSTM1) mediates diverse cellular functions including control of NFκB signaling and transcriptional activation. binds non-covalently to ubiquitin co-localizes with ubiquitylated inclusions in a number human aggregation diseases. Mutations the gene encoding cause Paget's disease bone (PDB), common disorder elderly characterized by excessive resorption formation. All PDB mutations identified date cluster within C-terminal region protein, which shows low sequence...
Abstract We have studied the effects of various PDB-causing mutations SQSTM1 on in vitro ubiquitin-binding properties p62 protein. All caused loss monoubiquitin-binding and impaired K48-linked polyubiquitin-binding, which was only evident at physiological temperature. This suggests that predispose to PDB through a common mechanism depends by p62. Introduction: Mutations gene, affect ubiquitin-associated (UBA) domain protein, are cause Paget's disease bone (PDB). previously showed isolated...
Abstract Mutations affecting the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) are commonly found in Paget's disease bone (PDB) and impair SQSTM1's ability to bind ubiquitin, resulting dysregulated NF-κB signaling. In contrast, non-UBA mutations rarer, little is known about how they manifest their effects. We present first characterization at molecular, cellular, functional level a missense mutation (A381V) SQSTM1. Direct sequencing exon 7 SQSTM1 gene an Italian PDB...
Ubiquitin (Ub) modifications are transduced by receptor proteins that use Ub-binding domains (UBDs) to recognize distinct interaction faces on the Ub surface. We report nuclear magnetic resonance (NMR) solution structures of A20-like zinc finger (A20 Znf) UBD ZNF216, and its complex with Ub, show binding surface centered Asp58 leaves canonical hydrophobic Ile44 patch free participate in additional interactions. have modeled ternary complexes different families UBDs while many expected bind...
Functional analyses of PDB (Paget's disease bone)-associated mutants the p62 [also known as SQSTM1 (sequestosome 1)] signalling adaptor protein represent an interesting paradigm for understanding not only mechanism in this skeletal disorder, but also critical determinants ubiquitin recognition by ubiquitin-binding protein. The 11 separate mutations identified to date all affect C-terminal region containing UBA domain (ubiquitin-associated domain), a element. All these have deleterious...
The conversion of signal transducer and activator transcription (STAT) proteins from latent to active factors is central cytokine signaling. Triggered by their signal-induced tyrosine phosphorylation, it the assembly a range cytokine-specific STAT homo- heterodimers that marks key step in transition hitherto activators. In contrast, constitutive self-assembly STATs how relates functioning activated understood less well. To provide more complete picture, we developed co-localization-based...
We show that the ubiquitin-associated domain (UBA) of human p62/sequestosome-1 (SQSTM1) can delay degradation proteasome substrates in yeast. Taking advantage naturally occurring mutant UBA domains are linked to Paget's disease bone (PDB), we found three four tested this study were able inhibit proteasomal degradation, albeit not same extent as wild-type domain. Interestingly, stability measured fraction folded protein, and ubiquitin binding properties, PDB-associated correlated with their...
Using the ASKA (A Complete Set of Escherichia coliK-12 ORF Archive) library for genome-wide screening E. coli proteins we identified that expression ygaQ and rpmG promotes mitomycin C resistance (MMCR). YgaQ mediated MMCR was independent homologous recombination involving RecA or RuvABC, but required UvrD. is an uncharacterized protein with α-amylases to have nuclease activity directed ssDNA 5′ flaps. Nuclease inactivated by mutation two amino acid motifs, which also abolished MMCR. RpmG...