Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Nat Commun
2021 May 14;121:2826. doi: 10.1038/s41467-021-22724-w.
Show Gene links
Show Anatomy links
Molecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases.
Kostritskii AY
,
Machtens JP
.
???displayArticle.abstract???
TMEM16 lipid scramblases transport lipids and also operate as ion channels with highly variable ion selectivities and various physiological functions. However, their molecular mechanisms of ion conduction and selectivity remain largely unknown. Using computational electrophysiology simulations at atomistic resolution, we identified the main ion-conductive state of TMEM16 lipid scramblases, in which an ion permeation pathway is lined by lipid headgroups that directly interact with permeating ions in a voltage polarity-dependent manner. We found that lipid headgroups modulate the ion-permeability state and regulate ion selectivity to varying degrees in different scramblase isoforms, depending on the amino-acid composition of the pores. Our work has defined the structural basis of ion conduction and selectivity in TMEM16 lipid scramblases and uncovered the mechanisms responsible for the direct effects of membrane lipids on the conduction properties of ion channels.
Alvadia,
Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F.
2019, Pubmed
Alvadia,
Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F.
2019,
Pubmed
Bethel,
Atomistic insight into lipid translocation by a TMEM16 scramblase.
2016,
Pubmed
,
Echinobase
Briones,
GROmaρs: A GROMACS-Based Toolset to Analyze Density Maps Derived from Molecular Dynamics Simulations.
2019,
Pubmed
Brunner,
X-ray structure of a calcium-activated TMEM16 lipid scramblase.
2014,
Pubmed
,
Echinobase
Bushell,
The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K.
2019,
Pubmed
Bussi,
Canonical sampling through velocity rescaling.
2007,
Pubmed
Cabrita,
Differential effects of anoctamins on intracellular calcium signals.
2017,
Pubmed
Caputo,
TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity.
2008,
Pubmed
Corradi,
Emerging Diversity in Lipid-Protein Interactions.
2019,
Pubmed
Dang,
Cryo-EM structures of the TMEM16A calcium-activated chloride channel.
2017,
Pubmed
,
Echinobase
Falzone,
Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase.
2019,
Pubmed
Feng,
Cryo-EM Studies of TMEM16F Calcium-Activated Ion Channel Suggest Features Important for Lipid Scrambling.
2019,
Pubmed
Grubb,
TMEM16F (Anoctamin 6), an anion channel of delayed Ca(2+) activation.
2013,
Pubmed
Gurtovenko,
Defect-mediated trafficking across cell membranes: insights from in silico modeling.
2010,
Pubmed
Huang,
CHARMM36m: an improved force field for folded and intrinsically disordered proteins.
2017,
Pubmed
Jeng,
Independent activation of distinct pores in dimeric TMEM16A channels.
2016,
Pubmed
Jiang,
Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase.
2017,
Pubmed
Juul,
Anoctamin 6 differs from VRAC and VSOAC but is involved in apoptosis and supports volume regulation in the presence of Ca2+.
2014,
Pubmed
Kalienkova,
Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM.
2019,
Pubmed
Khelashvili,
Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca2+-bound nhTMEM16.
2019,
Pubmed
,
Echinobase
Klauda,
Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types.
2010,
Pubmed
Kunzelmann,
Molecular functions of anoctamin 6 (TMEM16F): a chloride channel, cation channel, or phospholipid scramblase?
2014,
Pubmed
Kutzner,
Computational electrophysiology: the molecular dynamics of ion channel permeation and selectivity in atomistic detail.
2011,
Pubmed
Kutzner,
Insights into the function of ion channels by computational electrophysiology simulations.
2016,
Pubmed
Le,
An inner activation gate controls TMEM16F phospholipid scrambling.
2019,
Pubmed
Lee,
The nhTMEM16 Scramblase Is Also a Nonselective Ion Channel.
2016,
Pubmed
Lee,
Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase.
2018,
Pubmed
Lim,
Independent activation of ion conduction pores in the double-barreled calcium-activated chloride channel TMEM16A.
2016,
Pubmed
Lomize,
OPM database and PPM web server: resources for positioning of proteins in membranes.
2012,
Pubmed
Machtens,
Gating Charge Calculations by Computational Electrophysiology Simulations.
2017,
Pubmed
Malvezzi,
Ca2+-dependent phospholipid scrambling by a reconstituted TMEM16 ion channel.
2013,
Pubmed
Mansoor,
X-ray structures define human P2X(3) receptor gating cycle and antagonist action.
2016,
Pubmed
Martins,
Anoctamin 6 is an essential component of the outwardly rectifying chloride channel.
2011,
Pubmed
Michaud-Agrawal,
MDAnalysis: a toolkit for the analysis of molecular dynamics simulations.
2011,
Pubmed
Muller,
Characterization of Lipid-Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation.
2019,
Pubmed
Ousingsawat,
Anoctamin 6 mediates effects essential for innate immunity downstream of P2X7 receptors in macrophages.
2015,
Pubmed
Paulino,
Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM.
2017,
Pubmed
,
Echinobase
Pedemonte,
Structure and function of TMEM16 proteins (anoctamins).
2014,
Pubmed
Picollo,
TMEM16 proteins: unknown structure and confusing functions.
2015,
Pubmed
Pomorski,
Lipid flippases and their biological functions.
2006,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Scheurer,
PyContact: Rapid, Customizable, and Visual Analysis of Noncovalent Interactions in MD Simulations.
2018,
Pubmed
Schroeder,
Expression cloning of TMEM16A as a calcium-activated chloride channel subunit.
2008,
Pubmed
Scudieri,
Ion channel and lipid scramblase activity associated with expression of TMEM16F/ANO6 isoforms.
2015,
Pubmed
Shimizu,
TMEM16F is a component of a Ca2+-activated Cl- channel but not a volume-sensitive outwardly rectifying Cl- channel.
2013,
Pubmed
Taylor,
A major interspecies difference in the ionic selectivity of megakaryocyte Ca2+-activated channels sensitive to the TMEM16F inhibitor CaCCinh-A01.
2019,
Pubmed
Thompson,
CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.
1994,
Pubmed
Tian,
Anoctamins are a family of Ca2+-activated Cl- channels.
2012,
Pubmed
Vermeer,
Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.
2010,
Pubmed
Waterhouse,
Jalview Version 2--a multiple sequence alignment editor and analysis workbench.
2009,
Pubmed
Whitlock,
A Pore Idea: the ion conduction pathway of TMEM16/ANO proteins is composed partly of lipid.
2016,
Pubmed
Wolf,
g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation.
2010,
Pubmed
Yang,
TMEM16A confers receptor-activated calcium-dependent chloride conductance.
2008,
Pubmed
Yang,
TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation.
2012,
Pubmed
Ye,
Phosphatidylinositol-(4, 5)-bisphosphate regulates calcium gating of small-conductance cation channel TMEM16F.
2018,
Pubmed
Ye,
Dynamic change of electrostatic field in TMEM16F permeation pathway shifts its ion selectivity.
2019,
Pubmed
Yu,
Identification of a lipid scrambling domain in ANO6/TMEM16F.
2015,
Pubmed