TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

Nobuaki Takahashi; Sayaka Hamada-Nakahara; Yuzuru Itoh; Kazuhiro Takemura; Atsushi Shimada; Yoshifumi Ueda; Manabu Kitamata; Rei Matsuoka; Kyoko Hanawa-Suetsugu; Yosuke Senju; Masayuki X. Mori; Shigeki Kiyonaka; Daisuke Kohda; Akio Kitao; Yasuo Mori; Shiro Suetsugu

doi:10.1038/ncomms5994

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P₂

Nobuaki Takahashi, Sayaka Hamada-Nakahara, Yuzuru Itoh, Kazuhiro Takemura, Atsushi Shimada, Yoshifumi Ueda, Manabu Kitamata, Rei Matsuoka, Kyoko Hanawa-Suetsugu, Yosuke Senju, Masayuki X. Mori, Shigeki Kiyonaka, Daisuke Kohda, Akio Kitao, Yasuo Mori, Shiro Suetsugu

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Abstract

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.

Original language	English
Article number	4994
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5994
Publication status	Published - 2014
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms5994

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Takahashi, N., Hamada-Nakahara, S., Itoh, Y., Takemura, K., Shimada, A., Ueda, Y., Kitamata, M., Matsuoka, R., Hanawa-Suetsugu, K., Senju, Y., Mori, M. X., Kiyonaka, S., Kohda, D., Kitao, A., Mori, Y., & Suetsugu, S. (2014). TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P₂. Nature communications, 5, [4994]. https://doi.org/10.1038/ncomms5994

Takahashi, N, Hamada-Nakahara, S, Itoh, Y, Takemura, K, Shimada, A, Ueda, Y, Kitamata, M, Matsuoka, R, Hanawa-Suetsugu, K, Senju, Y, Mori, MX, Kiyonaka, S, Kohda, D, Kitao, A, Mori, Y & Suetsugu, S 2014, 'TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P₂', Nature communications, vol. 5, 4994. https://doi.org/10.1038/ncomms5994

@article{3c0a8600586942199799c9c8b63f1834,

title = "TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2",

abstract = "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.",

author = "Nobuaki Takahashi and Sayaka Hamada-Nakahara and Yuzuru Itoh and Kazuhiro Takemura and Atsushi Shimada and Yoshifumi Ueda and Manabu Kitamata and Rei Matsuoka and Kyoko Hanawa-Suetsugu and Yosuke Senju and Mori, {Masayuki X.} and Shigeki Kiyonaka and Daisuke Kohda and Akio Kitao and Yasuo Mori and Shiro Suetsugu",

note = "Funding Information: This work was partly performed in the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University. This research was supported by the Japan Society for the Promotion of Science (JSPS), through the {\textquoteleft}Funding Program for Next Generation World-Leading Researchers (NEXT Program){\textquoteright} initiated by the Council for Science and Technology Policy (CSTP) and also in part by the Next Generation Super Computing Project, Nanoscience Program, the Strategic Programs for Innovative Research (SPIRE) in Computational Material Science Initiative (CMSI), a Grant-in-Aid for Science Research B (23370066) and a Grant-in-Aid for Science Research in Innovative Areas (25104002), from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. The computational work in this report was conducted using the supercomputers at the Research Center for Computational Science, Okazaki Research Facilities, National Institute of Natural Science, our PC clusters, and the facilities at the Supercomputer Center, Institute for Solid State Physics, the University of Tokyo. We thank the staff members of the beam line for assistance with our data collection. The synchrotron radiation experiments were performed at the Photon Factory under the approval of the Photon Factory Program Advisory Committee (Proposal No. 2011G092, 2012G691) and at the SPring-8 under the approval of the Japan Synchrotron Radiation Research Institute (JASRI) (Proposal No. 2012B1242). Publisher Copyright: {\textcopyright}2014 Macmillan Publishers Limited. All rights reserved.",

year = "2014",

doi = "10.1038/ncomms5994",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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T1 - TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

AU - Takahashi, Nobuaki

AU - Hamada-Nakahara, Sayaka

AU - Itoh, Yuzuru

AU - Takemura, Kazuhiro

AU - Shimada, Atsushi

AU - Ueda, Yoshifumi

AU - Kitamata, Manabu

AU - Matsuoka, Rei

AU - Hanawa-Suetsugu, Kyoko

AU - Senju, Yosuke

AU - Mori, Masayuki X.

AU - Kiyonaka, Shigeki

AU - Kohda, Daisuke

AU - Kitao, Akio

AU - Mori, Yasuo

AU - Suetsugu, Shiro

N1 - Funding Information: This work was partly performed in the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University. This research was supported by the Japan Society for the Promotion of Science (JSPS), through the ‘Funding Program for Next Generation World-Leading Researchers (NEXT Program)’ initiated by the Council for Science and Technology Policy (CSTP) and also in part by the Next Generation Super Computing Project, Nanoscience Program, the Strategic Programs for Innovative Research (SPIRE) in Computational Material Science Initiative (CMSI), a Grant-in-Aid for Science Research B (23370066) and a Grant-in-Aid for Science Research in Innovative Areas (25104002), from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. The computational work in this report was conducted using the supercomputers at the Research Center for Computational Science, Okazaki Research Facilities, National Institute of Natural Science, our PC clusters, and the facilities at the Supercomputer Center, Institute for Solid State Physics, the University of Tokyo. We thank the staff members of the beam line for assistance with our data collection. The synchrotron radiation experiments were performed at the Photon Factory under the approval of the Photon Factory Program Advisory Committee (Proposal No. 2011G092, 2012G691) and at the SPring-8 under the approval of the Japan Synchrotron Radiation Research Institute (JASRI) (Proposal No. 2012B1242). Publisher Copyright: ©2014 Macmillan Publishers Limited. All rights reserved.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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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JO - Nature Communications

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ER -

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P₂

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