A plug release mechanism for membrane permeation by MLKL

Lijing Su, Bradley Quade, Huayi Wang, Liming Sun, Xiaodong Wang, Jose Rizo-Rey

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

MLKL is crucial for necroptosis, permeabilizing membranes through its N-terminal region upon phosphorylation of its kinase-like domain by RIP3. However, the mechanism underlying membrane permeabilization is unknown. The solution structure of the MLKL N-terminal region determined by nuclear magnetic resonance spectroscopy reveals a four-helix bundle with an additional helix at the top that is likely key for MLKL function, and a sixth, C-terminal helix that interacts with the top helix and with a poorly packed interface within the four-helix bundle. Fluorescence spectroscopy measurements indicate that much of the four-helix bundle inserts into membranes, but not the C-terminal helix. Moreover, we find that the four-helix bundle is sufficient to induce liposome leakage and that the C-terminal helix inhibits this activity. These results suggest that the four-helix bundle mediates membrane breakdown during necroptosis and that the sixth helix acts as a plug that prevents opening of the bundle and is released upon RIP3 phosphorylation.

Original languageEnglish (US)
Pages (from-to)1489-1500
Number of pages12
JournalStructure
Volume22
Issue number10
DOIs
StatePublished - Sep 13 2014

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Membranes
Phosphorylation
Fluorescence Spectrometry
Liposomes
Phosphotransferases
Magnetic Resonance Spectroscopy

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

A plug release mechanism for membrane permeation by MLKL. / Su, Lijing; Quade, Bradley; Wang, Huayi; Sun, Liming; Wang, Xiaodong; Rizo-Rey, Jose.

In: Structure, Vol. 22, No. 10, 13.09.2014, p. 1489-1500.

Research output: Contribution to journalArticle

Su, L, Quade, B, Wang, H, Sun, L, Wang, X & Rizo-Rey, J 2014, 'A plug release mechanism for membrane permeation by MLKL', Structure, vol. 22, no. 10, pp. 1489-1500. https://doi.org/10.1016/j.str.2014.07.014
Su, Lijing ; Quade, Bradley ; Wang, Huayi ; Sun, Liming ; Wang, Xiaodong ; Rizo-Rey, Jose. / A plug release mechanism for membrane permeation by MLKL. In: Structure. 2014 ; Vol. 22, No. 10. pp. 1489-1500.
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