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 language | English (US) |
|---|---|
| Pages (from-to) | 1489-1500 |
| Number of pages | 12 |
| Journal | Structure |
| Volume | 22 |
| Issue number | 10 |
| DOIs | |
| State | Published - Sep 13 2014 |
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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 journal › Article
}
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
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
VL - 22
SP - 1489
EP - 1500
JO - Structure with Folding & design
JF - Structure with Folding & design
SN - 0969-2126
IS - 10
ER -