A5049506396- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- Mitochondrial Function and Pathology
- Prion Diseases and Protein Misfolding
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Parkinson's Disease Mechanisms and Treatments
- HIV Research and Treatment
- Lysosomal Storage Disorders Research
- RNA and protein synthesis mechanisms
- Cell death mechanisms and regulation
- Cancer-related Molecular Pathways
- Protein Degradation and Inhibitors
- Glycosylation and Glycoproteins Research
- Advanced biosensing and bioanalysis techniques
- Mosquito-borne diseases and control
- CRISPR and Genetic Engineering
- Single-cell and spatial transcriptomics
- 14-3-3 protein interactions
- Histone Deacetylase Inhibitors Research
- MicroRNA in disease regulation
- Pancreatic function and diabetes
- Studies on Chitinases and Chitosanases
MRC Laboratory of Molecular Biology
2016-2025
Medical Research Council
2019
Addenbrooke's Hospital
2012-2015
University of Cambridge
2011-2014
Institute for Medical Research
2014
Wellcome Trust
2014
University of Michigan
2011
Abstract Endosomal protein sorting controls the localization of many physiologically important proteins and is linked to several neurodegenerative diseases. VPS35 a component retromer complex, which mediates endosome-to-Golgi retrieval membrane such as cation-independent mannose 6-phosphate receptor. Furthermore, also required for endosomal recruitment actin nucleation promoting WASH complex. The D620N mutation causes rare form autosomal-dominant Parkinson’s disease (PD). Here we show that...
Abstract Genome-wide association studies have identified several loci associated with Alzheimer’s disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which known substrate causatively linked AD, both vitro vivo . Furthermore, altered expression exacerbates...
We investigated how mitochondrial membrane proteins remain soluble in the cytosol until their delivery to mitochondria or degradation at proteasome. show that Ubiquilin family bind transmembrane domains prevent aggregation and temporarily allow opportunities for targeting. Over time, Ubiquilins recruit an E3 ligase ubiquitinate bound clients. The attached ubiquitin engages Ubiquilin's UBA domain, normally intramolecular UBL stabilizes Ubiquilin-client complex. This conformational change...
Abstract Autophagy is an important degradation pathway, which induced after starvation, where it buffers nutrient deprivation by recycling macromolecules in organisms from yeast to man. While the classical pathway mediating this response via mTOR inhibition, there are likely be additional pathways that support process. Here, we identify Annexin A2 as autophagy modulator regulates autophagosome formation enabling appropriate ATG9A trafficking endosomes autophagosomes actin. This process...
We have used misfolded prion protein (PrP*) as a model to investigate how mammalian cells recognize and degrade GPI-anchored proteins. While most membrane proteins are degraded by proteasomes, primarily in lysosomes. Quantitative flow cytometry analysis showed that at least 85% of PrP* molecules transiently access the plasma en route Unexpectedly, time-resolved quantitative proteomics revealed remarkably invariant interactome during its trafficking from endoplasmic reticulum (ER) Hence,...
In eukaryotic cells, half of all proteins function as subunits within multiprotein complexes. Imbalanced synthesis leads to unassembled intermediates that must be degraded minimize cellular toxicity. Here, we found excess PSMC5, a subunit the proteasome base, was targeted for degradation by HERC1 ubiquitin ligase in mammalian cells. identified PSMC5 its cognate assembly chaperone PAAF1. Because PAAF1 only dissociates after assembly, could also engage later such PSMC4-PSMC5-PAAF1 complex. A...
Cells contain numerous abundant molecular machines assembled from multiple subunits. Imbalances in subunit production and failed assembly generate orphan subunits that are eliminated by poorly defined pathways. Here, we determined how of the cytosolic chaperonin CCT recognized. Several unassembled recruited E3 ubiquitin ligase HERC2 using ZNRD2 as an adaptor. Both factors were necessary for degradation cells, sufficient ubiquitination with purified factors, optimal cell fitness. Domain...
The isolation of haploid cell lines has recently allowed the power forward genetic screens to be applied mammalian cells. interest in applying this powerful approach a system is only tempered by limited utility these screens, if confined lethal phenotypes. Here we expand scope approaches beyond live/dead and show that selection for surface phenotype via fluorescence-activated sorting can identify key molecules an intracellular pathway, case MHC class I antigen presentation. Non-lethal are...
Eukaryotic cells have evolved sophisticated quality control mechanisms to eliminate aggregation-prone proteins that compromise cellular health. Central this defense is the ubiquitin-proteasome system, where UBR4 acts as essential E4 ubiquitin ligase, amplifying degradation marks on defective proteins. Our cryo-EM analysis of in complex with its cofactors KCMF1 and CALM1 reveals a massive 1.3 MDa ring structure, featuring central substrate-binding arena flexibly attached catalytic units....
Summary Unassembled and partially assembled subunits of multi-protein complexes have emerged as major quality control clients, particularly under conditions imbalanced gene expression such stress, aging, aneuploidy. The factors mechanisms that eliminate orphan to maintain protein homeostasis are incompletely defined. Here, we show the UBR4-KCMF1 ubiquitin ligase complex is required for efficient degradation multiple unrelated from chaperonin, proteasome cap, core, a targeting complex....
Nature Communications 5:4998 doi: 10.1038/ncomms5998 (2014); Published 22 Sep 2014; Updated 28 Jan 2015 The following information was inadvertently omitted from the Methods section in this Article. Knockdown of atg7 zebrafish. Embryos were injected at one-cell stage with a translation blocking morpholino oligonucleotide targeted to start site (5′-GCTTCAGACTGGATTCCGCCATCGA-3′) or 5-bp mismatch control morpholino.