Next Article in Journal
Novel Glycerophospholipid, Lipo- and N-acyl Amino Acids from Bacteroidetes: Isolation, Structure Elucidation and Bioactivity
Next Article in Special Issue
The DNA Recognition Motif of GapR Has an Intrinsic DNA Binding Preference towards AT-rich DNA
Previous Article in Journal
The Role of Selected Natural Biomolecules in Sperm Production and Functionality
Previous Article in Special Issue
Coil Combination of Multichannel Single Voxel Magnetic Resonance Spectroscopy with Repeatedly Sampled In Vivo Data
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 26
Issue 17
10.3390/molecules26175194
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis

by
Yaqing Yang
1,2,
Encheng Xie
1,2,
Lingyu Du
1,
Yu Yang
1,2,
Bin Wu
3,
Liming Sun
1,2,
Shuqing Wang
4,* and
Bo OuYang
1,2,*
1
State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
2
University of Chinese Academy of Sciences, Beijing 100049, China
3
National Facility for Protein Science in Shanghai, ZhangJiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201203, China
4
School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(17), 5194; https://doi.org/10.3390/molecules26175194
Submission received: 13 July 2021 / Revised: 17 August 2021 / Accepted: 19 August 2021 / Published: 27 August 2021
(This article belongs to the Special Issue Biomolecular NMR 2021)
Browse Figures
Versions Notes

Abstract

Necroptosis is a type of programmed cell death executed through the plasma membrane disruption by mixed lineage kinase domain-like protein (MLKL). Previous studies have revealed that an N-terminal four-helix bundle domain (NBD) of MLKL is the executioner domain for the membrane permeabilization, which is auto-inhibited by the first brace helix (H6). After necroptosis initiation, this inhibitory brace helix detaches and the NBD can integrate into the membrane, and hence leads to necroptotic cell death. However, how the NBD is released and induces membrane rupture is poorly understood. Here, we reconstituted MLKL2–154 into membrane mimetic bicelles and observed the structure disruption and membrane release of the first brace helix that is regulated by negatively charged phospholipids in a dose-dependent manner. Using molecular dynamics simulation we found that the brace region in an isolated, auto-inhibited MLKL2–154 becomes intrinsically disordered in solution after 7 ns dynamic motion. Further investigations demonstrated that a cluster of arginines in the C-terminus of MLKL2–154 is important for the molecular conformational switch. Functional mutagenesis showed that mutating these arginines to glutamates hindered the membrane disruption of full-length MLKL and thus inhibited the necroptotic cell death. These findings suggest that the brace helix also plays an active role in MLKL regulation, rather than an auto-inhibitory domain.
Keywords: MLKL; brace helix; auto-inhibitory; MD simulation MLKL; brace helix; auto-inhibitory; MD simulation

Share and Cite

MDPI and ACS Style

Yang, Y.; Xie, E.; Du, L.; Yang, Y.; Wu, B.; Sun, L.; Wang, S.; OuYang, B. Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis. Molecules 2021, 26, 5194. https://doi.org/10.3390/molecules26175194

AMA Style

Yang Y, Xie E, Du L, Yang Y, Wu B, Sun L, Wang S, OuYang B. Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis. Molecules. 2021; 26(17):5194. https://doi.org/10.3390/molecules26175194

Chicago/Turabian Style

Yang, Yaqing, Encheng Xie, Lingyu Du, Yu Yang, Bin Wu, Liming Sun, Shuqing Wang, and Bo OuYang. 2021. "Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis" Molecules 26, no. 17: 5194. https://doi.org/10.3390/molecules26175194

APA Style

Yang, Y., Xie, E., Du, L., Yang, Y., Wu, B., Sun, L., Wang, S., & OuYang, B. (2021). Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis. Molecules, 26(17), 5194. https://doi.org/10.3390/molecules26175194

Article Metrics

Back to TopTop