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Articles by Michael Rape
Stimulated protein degradation to promote mitochondrial function and neuronal survival
Reference #1 Editor’s summary Structured Abstract Abstract Supplementary Materials References and Notes eLetters (0) Information & Authors Metrics & Citations Check Access References Figures Tables Media Share This article has 0 eLetter . Editor’s summary Mammalian cells have ubiquitin E3 ligases that detect defective proteins and promote their removal by proteolysis. Chandrasekhar et al.
Metabolite glues as a means of purine sensing and chemotherapeutic response
Abstract Molecular glues stabilize weak interactions to impart new functionalities to complexes1,2,3. Although molecular glues have been described in plant signalling and as human therapeutics4,5, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme in purine biosynthesis—phosphoribosyl pyrophosphate amidotransferase (PPAT)—to its inhibitor NUDT5.
The E3-ome gene-centric compendium reveals the human E3 ligase landscape
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Introduction E3s, the architects of protein ubiquitination, play a pivotal role in shaping the cellular landscape.
By Ngee Kiat Chua, Tania J. Gonzalez-Robles, Cameron J Reddington, Jane Dudley-Fraser, Richard W. Birkinshaw, Jiru Han, Ashleigh Solano, Tomasz Kochańczyk, Joshua Peter, Mark A. Nakasone, Florian Aust, Jacob Munro, Yeh Huei Tong, Julie Iskander, Waruni Abeysekera, Hannah Huckstep, Matthew Ritchie Verified, Ingrid E. Wertz, Sarah G. Hymowitz, Sharad Kumar, Gilbert G. Privé, Alex N. Bullock, Jeffrey J. Babon, Rachel E. Klevit, Sonja Lorenz, Alessio Ciulli, Eric S. Fischer, Nicolas H. Thomä, Radosław Nowak, Brenda A. Schulman, Michael Rape, Katrin Rittinger, Melanie Bahlo, Joel P. Mackay, Peter D. Mace, Christopher D. Lima, Ronald T. Hay, David Komander, Bernhard Lechtenberg, Claudio A.P. Joazeiro, Michele Pagano, Kay H Hofmann, Rebecca Feltham, Alex Garnham, Ron C. Conaway, Julia K. Pagan
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Cell Press
Verified
Function and regulation of the mitochondrial stress response - Nature Structural & Molecular Biology
Abstract As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle.
Signs of damage that drive protein degradation
NEWS AND VIEWS 29 January 2025 Many environmental toxins damage proteins, which then must be removed to avoid dangerous protein aggregation and disease. How cells dispose of chemically modified proteins has been unclear, but a discovery offers some clues. All organisms are constantly exposed to a barrage of environmental insults that can compromise the integrity of cells and tissues.
Reactive oxygen species control protein degradation at the mitochondrial import gate
Keywords ubiquitin proteasome reductive stress response TOM complex electron transport chain mitochondria FEM1B Introduction Toxins, protein aggregates, or mutations in metabolic pathways can lead to an accumulation of reactive oxygen species (ROS).1,2 Such pathological ROS damage proteins, lipids, and nucleic acids, which compromises genome or membrane integrity3,4,5,6 and has been associated with aging, cancer, and neurodegenerative disease.1,7,8 Oxidative stress responses help cells...
Dynamic regulation of the oxidative stress response by the E3 ligase TRIP12
Abstract The oxidative stress response is centered on the transcription factor NRF2 and protects cells from reactive oxygen species (ROS). While ROS inhibit the E3 ligase CUL3-KEAP1 to stabilize NRF2 and elicit antioxidant gene expression, cells recovering from stress must rapidly reactivate CUL3-KEAP1 to prevent reductive stress and oxeiptosis-dependent cell death. How cells restore efficient NRF2-degradation upon ROS clearance remains poorly understood.
Quality control of protein complex composition
Summary Eukaryotic cells possess hundreds of protein complexes that contain multiple subunits and must be formed at the correct time and place during development. Despite specific assembly pathways, cells frequently encounter complexes with missing or aberrant subunits that can disrupt important signaling events. Cells, therefore, employ several ubiquitin-dependent quality control pathways that can prevent, correct, or degrade flawed complexes.
Co-adaptor driven assembly of a CUL3 E3 ligase complex
Highlights • The co-adaptor subunit PEF1 drives CUL3KLHL12 complex formation. • PEF1 releases the adaptor KLHL12 from a CRL3 assembly inhibitor, Lunapark. • PEF1 monoubiquitylation stabilizes CUL3KLHL12 for efficient substrate modification. • USP9X cleaves ubiquitin off PEF1 to restrict CUL3KLHL12 activation. Summary Cullin-RING E3 ligases (CRLs) are essential ubiquitylation enzymes that combine a catalytic core built around cullin scaffolds with ∼300 exchangeable substrate adaptors.
An E3 ligase guide to the galaxy of small-molecule-induced protein degradation
Alazami A.M. Al-Saif A. Al-Semari A. Bohlega S. Zlitni S. Alzahrani F. Bavi P. Kaya N. Colak D. Khalak H. et al. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am. J. Hum. Genet. 2008; 83: 684-691 Angers S. Li T. Yi X. MacCoss M.J. Moon R.T. Zheng N. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature. 2006; 443: 590-593 Baek K. Krist D.T. Prabu J.R. Hill S. Klugel M.
A Cellular Mechanism to Detect and Alleviate Reductive Stress
Highlights • Lack of reactive oxygen species, or reductive stress, prevents myogenesis • Reductive stress reverses oxidation of invariant Cys residues in FNIP1 • Only reduced, but not oxidized, FNIP1 is polyubiquitylated by CUL2FEM1B • FNIP1 degradation leads to activation of mitochondria to recalibrate ROS Summary Metazoan organisms rely on conserved stress response pathways to alleviate adverse conditions and preserve cellular integrity.
Getting Close: Insight into the Structure and Function of K11/K48-Branched Ubiquitin Chains
K11/K48-branched ubiquitin chains are proteasomal priority signals that elicit the rapid elimination of mitotic regulators and aggregation-prone proteins. Indicative of an intriguing signaling mode, Boughton et al. (2019) Boughton A.J. Krueger S. Fushman D. Branching via K11 and K48 bestows ubiquitin chains with a unique interdomain interface and enhanced affinity for proteasomal subunit Rpn1. Structure.
Tug of War in the Xenophagy World
Xenophagy, the process of eliminating intracellular pathogens through the autophagy machinery, is an important defense mechanism against infectious disease, yet the underlying molecular mechanisms remain incompletely understood. Recent work (Xu et al., Cell, 2019) used the discovery of an inhibitor of xenophagy, SopF, to identify a SopF-sensitive mechanism that allows mammalian cells to detect invading bacteria.
Branching Out: Improved Signaling by Heterotypic Ubiquitin Chains
Allis C.D. Jenuwein T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 2016; 17: 487-500 Rape M. Ubiquitylation at the crossroads of development and disease. Nat. Rev. Mol. Cell Biol. 2017; 19: 59-70 Yau R. Rape M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 2016; 18: 579-586 Chau V. et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science. 1989; 243: 1576-1583 Jin L. et al.
Ubiquitin-Dependent Regulation of Stem Cell Biology
Ubiquitylation controls stem cell self-renewal by restricting the presentation of receptor complexes that can detect niche signals and by controlling the stability of transcription factors that determine cell fate. Ubiquitin-dependent signaling also governs the reversible exit from the cell cycle into a quiescent state, often by targeting cell-cycle regulators and transcription factors for degradation.
Getting a Grip on Microtubules
Posttranslational modifications control microtubule behavior, yet assigning roles to particular signals was hampered by lack of defined in vitro systems. In this issue of Cell, Valenstein and Roll-Mecak establish a biochemical platform to interrogate consequences of microtubule polyglutamylation, thereby providing important insights into the specificity and quantitative nature of cellular information transfer.
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