Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2

被引:31
作者
Goretzki, Benedikt [1 ,2 ]
Glogowski, Nina A. [1 ,2 ]
Diehl, Erika [1 ,2 ]
Duchardt-Ferner, Elke [2 ,3 ]
Hacker, Carolin [2 ,3 ]
Gaudet, Rachelle [4 ]
Hellmich, Ute A. [1 ,2 ]
机构
[1] Johannes Gutenberg Univ Mainz, Inst Pharm & Biochem, D-55128 Mainz, Germany
[2] Goethe Univ, Ctr Biomol Magnet Resonance BMRZ, D-60438 Frankfurt, Germany
[3] Goethe Univ, Inst Mol Biosci, D-60438 Frankfurt, Germany
[4] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA
关键词
SH3; DOMAIN; NMR-SPECTROSCOPY; PROTEIN BACKBONE; CATION CHANNEL; TORSION ANGLES; ION-CHANNEL; BINDING; ACTIVATION; GRADIENT; LIGAND;
D O I
10.1016/j.str.2018.08.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Transient receptor potential (TRP) channels are poly-modally regulated ion channels. TRPV4 (vanilloid 4) is sensitized by PIP2 and desensitized by Syndapin3/PACSIN3, which bind to the structurally uncharacterized TRPV4 N terminus. We determined the nuclear magnetic resonance structure of the Syndapin3/PACSIN3 SH3 domain in complex with the TRPV4 N-terminal proline-rich region (PRR), which binds as a class I polyproline II (PPII) helix. This PPII conformation is broken by a conserved proline in a cis conformation. Beyond the PPII, we find that the proximal TRPV4 N terminus is unstructured, a feature conserved across species thus explaining the difficulties in resolving it in previous structural studies. Syndapin/PACSIN SH3 domain binding leads to rigidification of both the PRR and the adjacent PIP2 binding site. We determined the affinities of the TRPV4 N terminus for PACSIN1, 2, and 3 SH3 domains and PIP2 and deduce a hierarchical interaction network where Syndapin/PACSIN binding influences the PIP2 binding site but not vice versa.
引用
收藏
页码:1583 / +
页数:16
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