ArticleProceedings of the National Academy of Sciences of the United States of America2020
Identification of MLKL membrane translocation as a checkpoint in necroptotic cell death using Monobodies.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 92 citations in OpenAlex.
- Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.IUBMB life · 2026Review
- The kinase domain of RIPK3 tunes its scaffolding functions.Cell death and differentiation · 2026Article
- Integrated Necroptosis Within Programmed Cell Death in Traumatic Brain Injury.Molecular neurobiology · 2026Review
- Identification of human MLKL Cys184 and HSPBP1 Cys201 as novel cellular targets for necroptosis.Cell death & disease · 2026Article
- Autoinhibitory control of MLKL governs pseudokinase domain phosphorylation and oligomerization during necroptosis.Cell reports · 2026Article
- Targeting MLKL-Driven Necroptosis: A Therapeutic Target in Inflammation and Host Defense.Biomolecules · 2026Review
- Unconventional binding of calmodulin to CHK2 kinase inhibits catalytic activity.The Biochemical journal · 2025Article
- Targeting PANoptosis: a promising therapeutic strategy for ALI/ARDS.Apoptosis : an international journal on programmed cell death · 2025Review
- Loss of Beclin 1 primes colorectal cancer cells for Immunogenic necroptosis via transcriptional de-repression of RIPK1/RIPK3/MLKL axis.Molecular biology reports · 2025Article
- Mixed Lineage Kinase Domain-Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Lipid nanoparticle-delivered intrabodies for inhibiting necroptosis and pyroptosis.The Biochemical journal · 2025Article
- Lytic coelomocyte death is tuned by cleavage but not phosphorylation of MLKL in echinoderms.PLoS pathogens · 2025Article
- Inhibition of RIPK1 or RIPK3 kinase activity post ischemia-reperfusion reduces the development of chronic kidney injury.The Biochemical journal · 2025Article
- Receptor-Interacting Protein Kinase 3-Mediated Modulation of Endothelial Cell Necroptosis and Mitochondrial Dysfunction through AMPK/Drp1 Signaling Pathway: Insights into the Pathophysiological Mechanisms of Lipopolysaccharide-Induced Acute Lung Injury.International journal of medical sciences · 2025Article
- CXCL8 Knockout: A Key to ResistingInternational journal of molecular sciences · 2024Article
- Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity.Nature reviews. Cancer · 2024Review
- Necroptosis inhibitors: mechanisms of action and therapeutic potential.Apoptosis : an international journal on programmed cell death · 2024Review
- Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo.Cell death & disease · 2024Article
- LUBAC-mediated M1 Ub regulates necroptosis by segregating the cellular distribution of active MLKL.Cell death & disease · 2024Article
- Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.Nature communications · 2023Article
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Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The necroptosis cell death pathway has been implicated in host defense and in the pathology of inflammatory diseases. While phosphorylation of the necroptotic effector pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) by the upstream protein kinase RIPK3 is a hallmark of pathway activation, the precise checkpoints in necroptosis signaling are still unclear. Here we have developed monobodies, synthetic binding proteins, that bind the N-terminal four-helix bundle (4HB) "killer" domain and neighboring first brace helix of human MLKL with nanomolar affinity. When expressed as genetically encoded reagents in cells, these monobodies potently block necroptotic cell death. However, they did not prevent MLKL recruitment to the "necrosome" and phosphorylation by RIPK3, nor the assembly of MLKL into oligomers, but did block MLKL translocation to membranes where activated MLKL normally disrupts membranes to kill cells. An X-ray crystal structure revealed a monobody-binding site centered on the α4 helix of the MLKL 4HB domain, which mutational analyses showed was crucial for reconstitution of necroptosis signaling. These data implicate the α4 helix of its 4HB domain as a crucial site for recruitment of adaptor proteins that mediate membrane translocation, distinct from known phospholipid binding sites.
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