Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase
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, a...
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doaj-d8de76d559d7421aaf3e8ebaa4d6e9a62021-05-05T17:19:21ZengeLife Sciences Publications LtdeLife2050-084X2019-01-01810.7554/eLife.43229Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblaseMaria E Falzone0https://orcid.org/0000-0001-6738-7017Jan Rheinberger1https://orcid.org/0000-0002-9901-2065Byoung-Cheol Lee2Thasin Peyear3Linda Sasset4Ashleigh M Raczkowski5Edward T Eng6https://orcid.org/0000-0002-8014-7269Annarita Di Lorenzo7Olaf S Andersen8Crina M Nimigean9https://orcid.org/0000-0002-6254-4447Alessio Accardi10https://orcid.org/0000-0002-6584-0102Department of Biochemistry, Weill Cornell Medical College, New York, United StatesDepartment of Anesthesiology, Weill Cornell Medical College, New York, United StatesDepartment of Anesthesiology, Weill Cornell Medical College, New York, United States; Department of Structure and Function on Neural Network, Korea Brain Research Institute, Deagu, Republic of KoreaDepartment of Physiology and Biophysics, Weill Cornell Medical College, New York, United StatesDepartment of Pathology, Weill Cornell Medical College, New York, United StatesSimons Electron Microscopy Center, New York Structural Biology Center, New York, United StatesSimons Electron Microscopy Center, New York Structural Biology Center, New York, United StatesDepartment of Pathology, Weill Cornell Medical College, New York, United StatesDepartment of Physiology and Biophysics, Weill Cornell Medical College, New York, United StatesDepartment of Biochemistry, Weill Cornell Medical College, New York, United States; Department of Anesthesiology, Weill Cornell Medical College, New York, United States; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, United StatesDepartment of Biochemistry, Weill Cornell Medical College, New York, United States; Department of Anesthesiology, Weill Cornell Medical College, New York, United States; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, United StatesThe 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 Ca2+-activated scramblases, but the mechanisms underlying their Ca2+-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 Aspergillus fumigatus, afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca2+-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.https://elifesciences.org/articles/43229Scramblingmembrane structuremembrane channelsphospholipids |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maria 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 |
spellingShingle |
Maria 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 Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase eLife Scrambling membrane structure membrane channels phospholipids |
author_facet |
Maria 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 |
author_sort |
Maria E Falzone |
title |
Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase |
title_short |
Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase |
title_full |
Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase |
title_fullStr |
Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase |
title_full_unstemmed |
Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase |
title_sort |
structural basis of ca2+-dependent activation and lipid transport by a tmem16 scramblase |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2019-01-01 |
description |
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 Ca2+-activated scramblases, but the mechanisms underlying their Ca2+-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 Aspergillus fumigatus, afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca2+-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. |
topic |
Scrambling membrane structure membrane channels phospholipids |
url |
https://elifesciences.org/articles/43229 |
work_keys_str_mv |
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1721459364654481408 |