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Proc Natl Acad Sci U S A
2016 Oct 18;11342:11847-11852. doi: 10.1073/pnas.1613523113.
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A competing hydrophobic tug on L596 to the membrane core unlatches S4-S5 linker elbow from TRP helix and allows TRPV4 channel to open.
Teng J
,
Loukin SH
,
Anishkin A
,
Kung C
.
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We have some generalized physical understanding of how ion channels interact with surrounding lipids but few detailed descriptions on how interactions of particular amino acids with contacting lipids may regulate gating. Here we discovered a structure-specific interaction between an amino acid and inner-leaflet lipid that governs the gating transformations of TRPV4 (transient receptor potential vanilloid type 4). Many cation channels use a S4-S5 linker to transmit stimuli to the gate. At the start of TRPV4's linker helix is leucine 596. A hydrogen bond between the indole of W733 of the TRP helix and the backbone oxygen of L596 secures the helix/linker contact, which acts as a latch maintaining channel closure. The modeled side chain of L596 interacts with the inner lipid leaflet near the polar-nonpolar interface in our model-an interaction that we explored by mutagenesis. We examined the outward currents of TRPV4-expressing Xenopus oocyte upon depolarizations as well as phenotypes of expressing yeast cells. Making this residue less hydrophobic (L596A/G/W/Q/K) reduces open probability [Po; loss-of-function (LOF)], likely due to altered interactions at the polar-nonpolar interface. L596I raises Po [gain-of-function (GOF)], apparently by placing its methyl group further inward and receiving stronger water repulsion. Molecular dynamics simulations showed that the distance between the levels of α-carbons of H-bonded residues L596 and W733 is shortened in the LOFs and lengthened in the GOFs, strengthening or weakening the linker/TRP helix latch, respectively. These results highlight that L596 lipid attraction counteracts the latch bond in a tug-of-war to tune the Po of TRPV4.
Anishkin,
Symmetry-restrained molecular dynamics simulations improve homology models of potassium channels.
2010,
Pubmed
Battle,
Lipid-protein interactions: Lessons learned from stress.
2015,
Pubmed
Cao,
TRPV1 structures in distinct conformations reveal activation mechanisms.
2013,
Pubmed
Eswar,
Comparative protein structure modeling using MODELLER.
2007,
Pubmed
Fagerberg,
Prediction of the human membrane proteome.
2010,
Pubmed
Gao,
TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action.
2016,
Pubmed
Gietz,
Large-scale high-efficiency yeast transformation using the LiAc/SS carrier DNA/PEG method.
2007,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Klauda,
Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types.
2010,
Pubmed
Kyte,
A simple method for displaying the hydropathic character of a protein.
1982,
Pubmed
Liao,
Structure of the TRPV1 ion channel determined by electron cryo-microscopy.
2013,
Pubmed
Liedtke,
Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.
2000,
Pubmed
Lin,
Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.
2012,
Pubmed
Long,
Voltage sensor of Kv1.2: structural basis of electromechanical coupling.
2005,
Pubmed
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Loukin,
Wild-type and brachyolmia-causing mutant TRPV4 channels respond directly to stretch force.
2010,
Pubmed
,
Xenbase
Loukin,
Hypotonic shocks activate rat TRPV4 in yeast in the absence of polyunsaturated fatty acids.
2009,
Pubmed
Loukin,
A channelopathy mechanism revealed by direct calmodulin activation of TrpV4.
2015,
Pubmed
,
Xenbase
Loukin,
Forward genetic analysis reveals multiple gating mechanisms of TRPV4.
2010,
Pubmed
,
Xenbase
Loukin,
Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations.
2011,
Pubmed
,
Xenbase
Lundbaek,
Membrane stiffness and channel function.
1996,
Pubmed
MacKerell,
All-atom empirical potential for molecular modeling and dynamics studies of proteins.
1998,
Pubmed
Manavalan,
Hydrophobic character of amino acid residues in globular proteins.
1978,
Pubmed
Nilius,
The puzzle of TRPV4 channelopathies.
2013,
Pubmed
Paulsen,
Structure of the TRPA1 ion channel suggests regulatory mechanisms.
2015,
Pubmed
Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed
Phillips,
Emerging roles for lipids in shaping membrane-protein function.
2009,
Pubmed
Reeves,
Membrane mechanics as a probe of ion-channel gating mechanisms.
2008,
Pubmed
Rostkowski,
Graphical analysis of pH-dependent properties of proteins predicted using PROPKA.
2011,
Pubmed
Schmidt,
Mechanistic basis for low threshold mechanosensitivity in voltage-dependent K+ channels.
2012,
Pubmed
,
Xenbase
Schmidt,
Voltage-dependent K+ channel gating and voltage sensor toxin sensitivity depend on the mechanical state of the lipid membrane.
2008,
Pubmed
,
Xenbase
Strotmann,
OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity.
2000,
Pubmed
Sweet,
Correlation of sequence hydrophobicities measures similarity in three-dimensional protein structure.
1983,
Pubmed
Teng,
Yeast luminometric and Xenopus oocyte electrophysiological examinations of the molecular mechanosensitivity of TRPV4.
2013,
Pubmed
,
Xenbase
Teng,
L596-W733 bond between the start of the S4-S5 linker and the TRP box stabilizes the closed state of TRPV4 channel.
2015,
Pubmed
,
Xenbase
Zubcevic,
Cryo-electron microscopy structure of the TRPV2 ion channel.
2016,
Pubmed