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  • Journal article

  • Chemical Proteomics Reveals Protein Tyrosination Extends Beyond the Alpha-Tubulins in Human Cells

    • Authors : Makarov, Dmytro  (2023)

  • Tubulin detyrosination-tyrosination cycle regulates the stability of microtubules. Thus far described on α-tubulins, the tyrosination level is maintained by a single tubulin-tyrosine ligase (TTL). However, the precise dynamics and tubulin isoforms which undergo (de)tyrosination in neurons are unknown. Here, we exploit the substrate promiscuity of the TTL to introduce an O-propargyl-L-tyrosine in neuroblastoma cells and neurons. Mass spectrometry-based chemical proteomics in neuroblas...
  • Journal article

  • Sulfotyrosine, an interaction specificity determinant for extracellular protein-protein interactions

    • Authors : Stewart, Valley (2023)

  • Tyrosine sulfation, a post-translational modification, can enhance and often determine protein-protein interaction specificity. Sulfotyrosyl residues (sTyr) are formed by tyrosylprotein sulfotransferase during maturation in the golgi apparatus, and most often occur singly or as a cluster of two or three sTyr within a six-residue span. With both negative charge and aromatic character, sTyr enables numerous atomic contacts as visualized in binding interfac...
  • Journal article

  • System-wide profiling by proteome integral solubility alteration assay of drug residence times for target characterization

    • Authors : Sabatier, Pierre (2023)

  • Most drugs used in the clinic and drug candidates target multiple proteins, and thus detailed characterization of their efficacy targets is required. While current methods rely on quantitative measurements at thermodynamic equilibrium, kinetic parameters such as the residence time of a drug on its target provide a better proxy for efficacy in vivo. Here, we present Residence Time Proteome Integral Solubility Alteration (ResT-PISA) assay which provides monitor...
  • Journal article

  • A conformational-dependent interdomain redox relay at the core of Protein Disulfide Isomerase activity

    • Authors : Melo, Eduardo P. (2023)

  • Protein disulfide isomerases (PDIs) are a family of molecular chaperones resident in the endoplasmic reticulum (ER) emerging as important factors in disease. In addition to an holdase function, some members catalyse disulfide bond formation and isomerization, a crucial step for native folding and prevention of aggregation of misfolded proteins. PDIs are characterized by a modular arrangement of thioredoxin-like domains, with the canonical, first identified PDIA1, ...
  • Journal article

  • Coenzyme A binding sites induce proximal acylation across protein families

    • Authors : Carrico, Chris (2023)

  • Lysine Nɛ-acylations, such as acetylation or succinylation, are post-translational modifications that regulate protein function. In mitochondria, lysine acylation is predominantly non-enzymatic, and only a specific subset of the proteome is acylated. Coenzyme A (CoA) can act as an acyl group carrier via a thioester bond, but what controls the acylation of mitochondrial lysines remains poorly understood. Using published datasets, here we found that pr...
  • Journal article

  • Ambient temperature crystal structure of Escherichia coli CyaY protein displays alternate conformation

    • Authors : Shafiei, Alaleh (2023)

  • Frataxin is a 23 KDa mitochondrial iron-binding protein that is involved in biogenesis of iron sulfur clusters. A deficiency in frataxin leads to Friedreich's ataxia, a progressive neurodegenerative disorder. The bacterial ortholog of eukaryotic mitochondrial frataxin, CyaY, is thought to play a role in iron sulfur cluster assembly as an iron supplier, making it an important target for study. Here, we present the first ambient tem...
  • Journal article

  • Chemoproteomics-Enabled Discovery of a Covalent Molecular Glue Degrader Targeting NF-κB

    • Authors : King, Elizabeth A. (2023)

  • Targeted protein degradation using heterobifunctional Proteolysis-Targeting Chimeras (PROTACs) or molecular glues has arisen as a powerful therapeutic modality for degrading disease targets. While PROTAC design is becoming more modular and straightforward, the discovery of novel molecular glue degraders has been more challenging. While several recent studies have showcased phenotypic screening and counter-screening approaches to discover new molecular glue degraders, me...
  • Journal Article

  • Evolving spike-protein N-glycosylation in SARS-CoV-2 variants

    • Authors :  Baboo, Sabyasachi (2023)

  • UBR4 is an E3 ligase (E3) of the N-degron pathway and is involved in neurodevelopment, age-associated muscular atrophy and cancer progression. The location and mechanistic classification of the E3 module within the 600 kDa protein UBR4 remains unknown. Herein, we identify and characterize, at a biochemical and structural level, a distinct E3 module within human UBR4 consisting of a novel “hemiRING” zinc finger, a helical-rich UBR ...