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TitleStructural basis of Ca-dependent activation and lipid transport by a TMEM16 scramblase.
Journal, issue, pagesElife, Vol. 8, Year 2019
Publish dateJan 16, 2019
AuthorsMaria E Falzone / Jan Rheinberger / Byoung-Cheol Lee / Thasin Peyear / Linda Sasset / Ashleigh M Raczkowski / Edward T Eng / Annarita Di Lorenzo / Olaf S Andersen / Crina M Nimigean / Alessio Accardi /
PubMed AbstractThe lipid distribution of plasma membranes of eukaryotic cells is asymmetric and phospholipid scramblases disrupt this asymmetry by mediating the rapid, nonselective transport of lipids down their ...The lipid distribution of plasma membranes of eukaryotic cells is asymmetric and phospholipid scramblases disrupt this asymmetry by mediating the rapid, nonselective transport of lipids down their concentration gradients. As a result, phosphatidylserine is exposed to the outer leaflet of membrane, an important step in extracellular signaling networks controlling processes such as apoptosis, blood coagulation, membrane fusion and repair. Several TMEM16 family members have been identified as Ca-activated scramblases, but the mechanisms underlying their Ca-dependent gating and their effects on the surrounding lipid bilayer remain poorly understood. Here, we describe three high-resolution cryo-electron microscopy structures of a fungal scramblase from , afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. These structures, together with functional experiments, suggest that activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement.
External linksElife / PubMed:30648972 / PubMed Central
MethodsEM (single particle)
Resolution3.59 - 4.05 Å
Structure data

EMDB-8931, PDB-6dz7:
afTMEM16 reconstituted in nanodiscs in the absence of Ca2+
Method: EM (single particle) / Resolution: 3.89 Å

EMDB-8948, PDB-6e0h:
PDB: afTMEM16 reconstituted in nanodiscs in the presence of Ca2+
Method: EM (single particle) / Resolution: 4.05 Å

EMDB-8959, PDB-6e1o:
afTMEM16 reconstituted in nanodiscs in the presence of Ca2+ and ceramide 24:0
Method: EM (single particle) / Resolution: 3.59 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-D12:
DODECANE

ChemComp-D10:
DECANE

ChemComp-8K6:
Octadecane

ChemComp-HEX:
HEXANE

Source
  • Aspergillus fumigatus (mold)
  • neosartorya fumigata (strain atcc mya-4609 / af293 / cbs 101355 / fgsc a1100) (mold)
KeywordsLIPID TRANSPORT / scramblase / Ca2+-activated / membrane-reorganization

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