PDBsum entry 3w9f

Transport protein

PDB id: 3w9f

Contents

Protein chains

255 a.a.

Ligands

I3P ×4

Waters ×461

PDB id:

3w9f

Name:

Transport protein

Title:

Crystal structure of the ankyrin repeat domain of chicken trpv4 in complex with ip3

Structure:

Vanilloid receptor-related osmotically activated channel protein. Chain: a, b, c, d. Fragment: unp residues 133-382. Engineered: yes

Source:

Gallus gallus. Bantam,chickens. Organism_taxid: 9031. Gene: trpv4, vr-oac. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.90Å R-factor: 0.219 R-free: 0.246

Authors:

Y.Itoh,S.Hamada-Nakahara,S.Suetsugu

Key ref:

N.Takahashi et al. (2014). TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P₂. Nat Commun, 5, 4994. PubMed id: 25256292 DOI: 10.1038/ncomms5994

Date:

04-Apr-13 Release date: 09-Apr-14

Protein chains

A0A1D5PXA5  (TRPV4_CHICK) -  Transient receptor potential cation channel subfamily V member 4 from Gallus gallus

Seq: 852 a.a.

Struc: 255 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1038/ncomms5994

Nat Commun 5:4994 (2014)

PubMed id: 25256292

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

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.

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.