2MSV

Solution structure of the MLKL N-terminal domain

Summary for 2MSV

• Entry DOI: 10.2210/pdb2msv/pdb
• NMR Information: BMRB: 25135
• Descriptor: Mixed lineage kinase domain-like protein (1 entity in total)
• Functional Keywords: membrane pore, membrane protein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q8NB16
• Total number of polymer chains: 1
• Total formula weight: 18896.78

Authors

Su, L.,Rizo, J.,Quade, B.,Wang, H.,Sun, L.,Wang, X. (deposition date: 2014-08-07, release date: 2014-09-24, Last modification date: 2024-05-01)

Primary citation

Su, L.,Quade, B.,Wang, H.,Sun, L.,Wang, X.,Rizo, J.
A Plug Release Mechanism for Membrane Permeation by MLKL.
Structure, 22:1489-1500, 2014

PubMed 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.

PubMed: 25220470
DOI: 10.1016/j.str.2014.07.014

Experimental method

SOLUTION NMR