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Title | Structural basis of closed groove scrambling by a TMEM16 protein. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 31, Issue 10, Page 1468-1481, Year 2024 |
Publish date | Apr 29, 2024 |
Authors | Zhang Feng / Omar E Alvarenga / Alessio Accardi / |
PubMed Abstract | Activation of Ca-dependent TMEM16 scramblases induces phosphatidylserine externalization, a key step in multiple signaling processes. Current models suggest that the TMEM16s scramble lipids by ...Activation of Ca-dependent TMEM16 scramblases induces phosphatidylserine externalization, a key step in multiple signaling processes. Current models suggest that the TMEM16s scramble lipids by deforming the membrane near a hydrophilic groove and that Ca dependence arises from the different association of lipids with an open or closed groove. However, the molecular rearrangements underlying groove opening and how lipids reorganize outside the closed groove remain unknown. Here we directly visualize how lipids associate at the closed groove of Ca-bound fungal nhTMEM16 in nanodiscs using cryo-EM. Functional experiments pinpoint lipid-protein interaction sites critical for closed groove scrambling. Structural and functional analyses suggest groove opening entails the sequential appearance of two π-helical turns in the groove-lining TM6 helix and identify critical rearrangements. Finally, we show that the choice of scaffold protein and lipids affects the conformations of nhTMEM16 and their distribution, highlighting a key role of these factors in cryo-EM structure determination. |
External links | Nat Struct Mol Biol / PubMed:38684930 |
Methods | EM (single particle) |
Resolution | 2.64 - 4.07 Å |
Structure data | EMDB-41453, PDB-8toi: EMDB-41454, PDB-8tok: EMDB-41455, PDB-8tol: EMDB-41457: nhTMEM16 lipid scramblase in lipid nanodiscs with MSP1E3 scaffold protein in the presence of Ca2+ (closed state) (consensus map) EMDB-41458: nhTMEM16 lipid scramblase in lipid nanodiscs with MSP1E3 scaffold protein in the presence of Ca2+ (closed state)(local refined monomer map) EMDB-41477, PDB-8tpm: EMDB-41478, PDB-8tpn: EMDB-41479, PDB-8tpo: EMDB-41480, PDB-8tpp: EMDB-41481, PDB-8tpq: EMDB-41482, PDB-8tpr: EMDB-41483, PDB-8tps: EMDB-41484, PDB-8tpt: |
Chemicals | ChemComp-CA: ChemComp-PGW: |
Source |
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Keywords | LIPID TRANSPORT / membrane protein / lipid scramblase / TMEM16 |