A5007485808- RNA and protein synthesis mechanisms
- Endoplasmic Reticulum Stress and Disease
- Bacterial Genetics and Biotechnology
- Monoclonal and Polyclonal Antibodies Research
- Radiopharmaceutical Chemistry and Applications
- RNA modifications and cancer
- Cellular transport and secretion
- Genetics, Bioinformatics, and Biomedical Research
- RNA Research and Splicing
- Cell Adhesion Molecules Research
- Peroxisome Proliferator-Activated Receptors
- Peptidase Inhibition and Analysis
- Toxin Mechanisms and Immunotoxins
- Bacteriophages and microbial interactions
- Photosynthetic Processes and Mechanisms
- Fungal and yeast genetics research
- Enzyme Production and Characterization
- Hepatitis B Virus Studies
- CAR-T cell therapy research
- Metabolism and Genetic Disorders
- Mitochondrial Function and Pathology
- Advanced Biosensing Techniques and Applications
- Heat shock proteins research
- Metabolism, Diabetes, and Cancer
- Signaling Pathways in Disease
University of Manchester
2012-2025
Manchester Academic Health Science Centre
2018-2024
Google (United States)
2020
Health Innovation Manchester
2018
Heidelberg University
1999-2006
Max Planck Institute for Molecular Genetics
2006
Howard Hughes Medical Institute
2006
Yale University
2006
University of Geneva
2003
DKFZ-ZMBH Alliance
1998-2002
Signal recognition particle (SRP), together with its receptor (SR), mediates the targeting of ribosome-nascent chain complexes to endoplasmic reticulum. Using protein cross-linking, we detected distinct modes in binding SRP ribosome. During signal peptide recognition, SRP54 is positioned at exit site close ribosomal proteins L23a and L35. When contacts SR, rearranged such that it no longer L23a. This repositioning may allow translocon dock ribosome, leading insertion into translocation channel.
Amino-terminal acetylation is probably the most common protein modification in eukaryotes with as many 50%-80% of proteins reportedly altered this way. Here we report a systematic analysis predicted N-terminal processing cytosolic versus those destined to be sorted secretory pathway. While were profoundly biased favour processing, found an equal and opposite bias against such for proteins. Mutations signal sequences that led their resulted mis-sorting cytosol manner was dependent upon...
BACKGROUND: Morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) is increased in metabolic disorders. However, options for preventing treating these prevalent outcomes are limited. Intramyocardial lipotoxicity contributes to cardiac dysfunction. Here, we investigate the mechanisms underlying endoplasmic reticulum degradation enhancing EDEM2 (endoplasmic degradation–enhancing alpha-mannosidase–like protein 2) regulation lipid homeostasis assess strategies that...
Signal sequences of secretory and membrane proteins are recognized by the signal recognition particle (SRP) as they emerge from ribosome. This results in their targeting to docking with SRP receptor, which facilitates transfer ribosome translocon. Here, we present 8 angstrom cryo-electron microscopy structure a "docking complex" consisting SRP-bound 80S receptor. Interaction receptor both rearranged S domain such that ribosomal binding site for translocon, L23e/L35 site, became exposed,...
Production and trafficking of proteins entering the secretory pathway eukaryotic cells is coordinated at endoplasmic reticulum (ER) in a process that begins with protein translocation via membrane-embedded ER translocon. The same complex also responsible for co-translational integration membrane orchestrates polypeptide modifications are often essential function. We now show previously identified inhibitor ER-associated degradation (ERAD) eeyarestatin 1 (ESI) potent translocation. have...
Scp160p is an RNA-binding protein containing 14 tandemly repeated heterogenous nuclear ribonucleoprotein K-homology domains, which are implicated in RNA binding. interacts with free and membrane-bound polysomes that dependent upon the presence of mRNA. Despite its on cytosolic polysomes, predominantly localized to endoplasmic reticulum (ER). Accumulation Scp160p-ribosome complexes at ER requires function microtubules but independent actin cytoskeleton. We propose multi-K-homology-domain...
Abstract Two distinct pathways deliver secretory proteins to the Sec61 protein translocase in endoplasmic reticulum membrane. The canonical pathway requires signal recognition particle (SRP) and its cognate receptor (SR), targets ribosome-associated Sec translocase. SRP-independent translocase-associated ER membrane Sec62 can be uncoupled from translation. Here we show that SR switches translocons SRP-dependent translocation by displacing Sec62. This activity localizes charged linker region...
The ribosome exit site is a focal point for the interaction of protein-biogenesis factors that guide fate nascent polypeptides. These include chaperones such as NAC, N-terminal-modifying enzymes like Methionine aminopeptidase (MetAP), and signal recognition particle (SRP), which targets secretory membrane proteins to ER. potentially compete with one another in short time-window when chain first emerges at site, suggesting need regulation. Here, we show MetAP contacts universal adaptor where...
Membrane protein integration occurs predominantly at the endoplasmic reticulum and is mediated by translocon, which formed Sec61p complex. The translocon binds to ribosome polypeptide exit site such that in a cotranslational manner. Ribosomal Rpl17 positioned it contacts both tunnel surface of near site, where intimately associated with translocon. presence trans-membrane (TM) segment inside ribosomal leads recruitment RAMP4 adjacent Rpl17. This suggests signaling function for can recognize...
Abstract We sequenced and characterized PMP22 (22-kDperoxisomal membrane protein) from Arabidopsis, which shares 28% to 30% amino acid identity 55% 57% similarity two related mammalian peroxisomal proteins, Mpv17. Subcellular fractionation studies confirmed that the Arabidopsis is a genuine protein. Biochemical analyses established an integral protein completely embedded in lipid bilayer. In vitro import assays demonstrated inserted into posttranslationally absence of ATP, but ATP stimulates...
Protein targeting to the membrane of ER is regulated by three GTPases, 54-kD subunit signal recognition particle (SRP) and alpha- beta-subunit SRP receptor (SR). Here, we report on GTPase cycle beta-subunits SR (SRbeta). We found that SRbeta binds GTP with high affinity interacts ribosomes in GTP-bound state. Subsequently, ribosome increases activity thus functions as a activating protein for SRbeta. Furthermore, interaction between leads reduction guanine nucleotides. propose regulates...
Multi-spanning membrane protein loops are directed alternately into the cytosol or ER lumen during cotranslational integration. Nascent chain exposure is switched after a newly synthesized transmembrane segment (TMS) enters ribosomal tunnel. FRET measurements revealed that each TMS initially extended, but folds compact conformation moving 6–7 residues from peptidyltransferase center, irrespective of loop size. The ribosome-induced folding coincided with its photocrosslinking to L17 and an...
The eukaryotic signal recognition particle (SRP) is essential for cotranslational targeting of proteins to the endoplasmic reticulum (ER). SRP Alu domain specifically required delaying nascent chain elongation upon sequence by and was therefore proposed interact directly with ribosomes. Using protein cross-linking, we provide experimental evidence that binding SRP14 in close physical proximity several ribosomal functional complexes. Cross-linking occurs even absence a demonstrating can bind...
Targeting of proteins to the endoplasmic reticulum (ER) occurs cotranslationally necessitating interaction signal recognition particle (SRP) and translocon with ribosome. Biochemical structural studies implicate ribosomal protein Rpl25p as a major ribosome site for both these factors. Here we characterize an RPL25GFP fusion, which behaves dominant mutant leading defects in co- but not posttranslational translocation vivo. In cells, ribosomes still interact ER membrane translocon, are...
Summary We have studied the import of proteins into glyoxysomes in vitro and show that this process is specifically inhibited by NADPH. NADPH affects both binding translocation glyoxysomes, inhibition determined ratio NADP + to The site action most likely within glyoxysome because (1) pretreatment with NADPH, followed re‐isolation organelles prior assay, resulted could be restored addition ; (2) low concentrations broken membranes. sensitivity protein declines as are converted leaf‐type...