ArticleNature communications2018
Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.
Article in Nature communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 118 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
118 citing papers in PubMed, 192 citations in OpenAlex.
- Necrostatin-1 Ameliorates Neutrophilic Inflammation in Asthma by Suppressing MLKL Phosphorylation to Inhibiting NETs Release.Frontiers in immunology · 2020Trial
- 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
- Review
- PANoptosis as a drug discovery framework: integrating cell death architecture with clinical translation.Genes and immunity · 2026Review
- 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
- PANoptosis as a Potential Therapeutic Target in Drug-Induced Liver Injury: A Narrative Review.Journal of inflammation research · 2026Review
- Monogenic disorders of the TNF signalling pathway.Nature reviews. Rheumatology · 2026Review
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
- Role of RIPK1/RIPK3/MLKL signalling pathway in sepsis-associated acute kidney injury.Experimental physiology · 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
- Article
- Lytic coelomocyte death is tuned by cleavage but not phosphorylation of MLKL in echinoderms.PLoS pathogens · 2025Article
- Necroptosis in obesity: a complex cell death event.Apoptosis : an international journal on programmed cell death · 2025Review
- MLKL-USP7-UBA52 signaling is indispensable for autophagy in brain through maintaining ubiquitin homeostasis.Autophagy · 2025Article
- Inhibition of RIPK1 or RIPK3 kinase activity post ischemia-reperfusion reduces the development of chronic kidney injury.The Biochemical journal · 2025Article
- For Better or Worse: The Impact of Necrotic Cell Death Modalities.Advances in experimental medicine and biology · 2025Review
- MLKL as an emerging machinery for modulating organelle dynamics: regulatory mechanisms, pathophysiological significance, and targeted therapeutics.Frontiers in pharmacology · 2025Review
58 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.
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.