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TitleCryo-EM Studies of TMEM16F Calcium-Activated Ion Channel Suggest Features Important for Lipid Scrambling.
Journal, issue, pagesCell Rep, Vol. 28, Issue 2, Page 567-579.e4, Year 2019
Publish dateJul 9, 2019
AuthorsShengjie Feng / Shangyu Dang / Tina Wei Han / Wenlei Ye / Peng Jin / Tong Cheng / Junrui Li / Yuh Nung Jan / Lily Yeh Jan / Yifan Cheng /
PubMed AbstractAs a Ca-activated lipid scramblase and ion channel that mediates Ca influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How ...As a Ca-activated lipid scramblase and ion channel that mediates Ca influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How a bona fide ion channel scrambles lipids remains elusive. Our structural analyses revealed the coexistence of an intact channel pore and PIP-dependent protein conformation changes leading to membrane distortion. Correlated to the extent of membrane distortion, many tightly bound lipids are slanted. Structure-based mutagenesis studies further reveal that neutralization of some lipid-binding residues or those near membrane distortion specifically alters the onset of lipid scrambling, but not Ca influx, thus identifying features outside of channel pore that are important for lipid scrambling. Together, our studies demonstrate that membrane distortion does not require open hydrophilic grooves facing the membrane interior and provide further evidence to suggest separate pathways for lipid scrambling and ion permeation.
External linksCell Rep / PubMed:31291589 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 3.9 Å
Structure data

20244

6p46

EMDB-20244, PDB-6p46:
Cryo-EM structure of TMEM16F in digitonin with calcium bound
Method: EM (single particle) / Resolution: 3.5 Å

20245

6p47

EMDB-20245, PDB-6p47:
Cryo-EM structure of TMEM16F in digitonin without calcium
Method: EM (single particle) / Resolution: 3.9 Å

20246

6p48

EMDB-20246, PDB-6p48:
Cryo-EM structure of calcium-bound TMEM16F in nanodisc with supplement of PIP2 in Cl1
Method: EM (single particle) / Resolution: 3.2 Å

20247

6p49

EMDB-20247, PDB-6p49:
Cryo-EM structure of calcium-bound TMEM16F in nanodisc with supplement of PIP2 in Cl2
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-CA:
Unknown entry

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / TMEM16F / scramblase

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