ArticleCell death and differentiation2018
The brace helices of MLKL mediate interdomain communication and oligomerisation to regulate cell death by necroptosis.
Article in Cell death and differentiation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
54 citing papers in PubMed, 99 citations in OpenAlex.
- Research Progress on NINJ1-Mediated Plasma Membrane Rupture Regulation of Pathogen Infection Process.International journal of molecular sciences · 2026Review
- Targeting MLKL-Driven Necroptosis: A Therapeutic Target in Inflammation and Host Defense.Biomolecules · 2026Review
- To Die or Not to Die: How Sublethal Damage Rewires Cell Fate and Implications for Sepsis.Journal of inflammation research · 2026Review
- Monogenic disorders of the TNF signalling pathway.Nature reviews. Rheumatology · 2026Review
- Targeting PANoptosis: a promising therapeutic strategy for ALI/ARDS.Apoptosis : an international journal on programmed cell death · 2025Review
- PANoptosis in hepatocellular carcinoma: Underlying mechanisms.World journal of hepatology · 2025Review
- Disrupting membranes, controlling cell fate: the role of pore-forming proteins in cell death and therapy.Apoptosis : an international journal on programmed cell death · 2025Review
- Mixed Lineage Kinase Domain-Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Zinc ions trigger PANoptosis-like cell death in magnetic hyperthermia therapy of magnesium based implant for hepatocellular carcinoma.Apoptosis : an international journal on programmed cell death · 2025Article
- Modeling Necroptotic and Pyroptotic Signaling inBiomolecules · 2025Review
- Lytic coelomocyte death is tuned by cleavage but not phosphorylation of MLKL in echinoderms.PLoS pathogens · 2025Article
- MLKL-USP7-UBA52 signaling is indispensable for autophagy in brain through maintaining ubiquitin homeostasis.Autophagy · 2025Article
- Necroptosis in obesity: a complex cell death event.Apoptosis : an international journal on programmed cell death · 2025Review
- MLKL as an emerging machinery for modulating organelle dynamics: regulatory mechanisms, pathophysiological significance, and targeted therapeutics.Frontiers in pharmacology · 2025Review
- For Better or Worse: The Impact of Necrotic Cell Death Modalities.Advances in experimental medicine and biology · 2025Review
- Exploring the critical role of PANoptosis in the pathogenesis of intervertebral disc degeneration: mechanisms and potential therapeutic targets.Frontiers in cell and developmental biology · 2025Review
- Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression.Molecular cancer · 2024Review
- Multifaceted role ofMedComm · 2024Review
- Targeting necroptosis: a promising avenue for respiratory disease treatment.Cell communication and signaling : CCS · 2024Review
- PANoptosis: bridging apoptosis, pyroptosis, and necroptosis in cancer progression and treatment.Cancer gene therapy · 2024Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The programmed cell death pathway, necroptosis, relies on the pseudokinase, Mixed Lineage Kinase domain-Like (MLKL), for cellular execution downstream of death receptor or Toll-like receptor ligation. Receptor-interacting protein kinase-3 (RIPK3)-mediated phosphorylation of MLKL's pseudokinase domain leads to MLKL switching from an inert to activated state, where exposure of the N-terminal four-helix bundle (4HB) 'executioner' domain leads to cell death. The precise molecular details of MLKL activation, including the stoichiometry of oligomer assemblies, mechanisms of membrane translocation and permeabilisation, remain a matter of debate. Here, we dissect the function of the two 'brace' helices that connect the 4HB to the pseudokinase domain of MLKL. In addition to establishing that the integrity of the second brace helix is crucial for the assembly of mouse MLKL homotrimers and cell death, we implicate the brace helices as a device to communicate pseudokinase domain phosphorylation event(s) to the N-terminal executioner 4HB domain. Using mouse:human MLKL chimeras, we defined the first brace helix and adjacent loop as key elements of the molecular switch mechanism that relay pseudokinase domain phosphorylation to the activation of the 4HB domain killing activity. In addition, our chimera data revealed the importance of the pseudokinase domain in conferring host specificity on MLKL killing function, where fusion of the mouse pseudokinase domain converted the human 4HB + brace from inactive to a constitutive killer of mouse fibroblasts. These findings illustrate that the brace helices play an active role in MLKL regulation, rather than simply acting as a tether between the 4HB and pseudokinase domains.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.