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 - 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
SN - 0969-2126
VL - 22
SP - 1489
EP - 1500
JO - Structure
JF - Structure
IS - 10
ER -