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PDBsum entry 3w9g
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Transport protein
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PDB id
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3w9g
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References listed in PDB file
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Key reference
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Title
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Trpv4 channel activity is modulated by direct interaction of the ankyrin domain to pi(4,5)p₂.
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Authors
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N.Takahashi,
S.Hamada-Nakahara,
Y.Itoh,
K.Takemura,
A.Shimada,
Y.Ueda,
M.Kitamata,
R.Matsuoka,
K.Hanawa-Suetsugu,
Y.Senju,
M.X.Mori,
S.Kiyonaka,
D.Kohda,
A.Kitao,
Y.Mori,
S.Suetsugu.
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Ref.
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Nat Commun, 2014,
5,
4994.
[DOI no: ]
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PubMed id
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Abstract
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Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for
several channelopathies, including Charcot-Marie-Tooth disease type 2C and
congenital distal and scapuloperoneal spinal muscular atrophy. However, the
molecular pathogenesis mediated by these mutations remains elusive, mainly due
to limited understanding of the TRPV4 ARD function. Here we show that
phosphoinositide binding to the TRPV4 ARD leads to suppression of the channel
activity. Among the phosphoinositides, phosphatidylinositol-4,5-bisphosphate
(PI(4,5)P2) most potently binds to the TRPV4 ARD. The crystal structure of the
TRPV4 ARD in complex with inositol-1,4,5-trisphosphate, the head-group of
PI(4,5)P2, and the molecular-dynamics simulations revealed the PI(4,5)P2-binding
amino-acid residues. The TRPV4 channel activities were increased by titration or
hydrolysis of membrane PI(4,5)P2. Notably, disease-associated TRPV4 mutations
that cause a gain-of-function phenotype abolished PI(4,5)P2 binding and
PI(4,5)P2 sensitivity. These findings identify TRPV4 ARD as a lipid-binding
domain in which interactions with PI(4,5)P2 normalize the channel activity in
TRPV4.
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