TY - JOUR
T1 - A plug release mechanism for membrane permeation by MLKL
AU - Su, Lijing
AU - Quade, Bradley
AU - Wang, Huayi
AU - Sun, Liming
AU - Wang, Xiaodong
AU - Rizo-Rey, Jose
N1 - Funding Information:
The DD2 console of one of the Agilent 600 MHz NMR spectrometers used for the research presented here was purchased with shared instrumentation grant S10RR026461 from the NIH (to Michael K. Rosen). This work was supported by grant I-1304 from the Welch Foundation (to J.R.) and NIH grant NS040944 (to J.R.).
Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
PY - 2014/9/13
Y1 - 2014/9/13
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2014.07.014
DO - 10.1016/j.str.2014.07.014
M3 - Article
C2 - 25220470
AN - SCOPUS:84908173839
VL - 22
SP - 1489
EP - 1500
JO - Structure with Folding & design
JF - Structure with Folding & design
SN - 0969-2126
IS - 10
ER -