Related Experiment Video

Updated: Sep 11, 2025

Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein
11:23

Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein

Published on: June 30, 2019

6.3K

Mixed Lineage Kinase Domain-Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities

Lijuan Xu1, Chunlin Zhuang1,2

  • 1The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|August 11, 2025
PubMed

Insights

Regulated cell death involves the mixed lineage kinase domain-like protein (MLKL) executing necroptosis. This review details MLKL activation, its transition to a membrane-embedded state, and therapeutic targeting strategies.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Biochemistry

Background:

  • Regulated cell death (RCD) pathways utilize executioner proteins for lytic cell death.
  • Mixed lineage kinase domain-like protein (MLKL) is the key executioner in necroptosis.
  • MLKL activation is a multi-step process involving phosphorylation and oligomerization.

Purpose of the Study:

  • To review the specific mechanisms of MLKL activation across different species.
  • To describe the transition of MLKL from an auto-inhibited state to a membrane-embedded form.
  • To explore therapeutic strategies targeting MLKL.

Main Methods:

  • Literature review of MLKL activation pathways.
  • Analysis of protein-protein and protein-lipid interactions in necroptosis.
  • Discussion of MLKL targeting approaches.

Main Results:

  • MLKL activation involves sequential steps: phosphorylation by RIPK3, oligomerization, membrane recruitment, and insertion.
  • MLKL forms membrane hotspots crucial for cell lysis.
  • Species-specific variations in MLKL activation mechanisms exist.

Conclusions:

  • Understanding MLKL activation is critical for deciphering necroptosis.
  • MLKL represents a promising therapeutic target for diseases involving necroptosis.
  • Further research into MLKL-targeting inhibitors and interacting proteins is warranted.
Keywords:
4HBMLKLMLKL inhibitorsactivation mechanismspseudokinase domain

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