Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP 2

Transient receptor potential (TRP) channels are polymodally regulated ion channels. TRPV4 (vanilloid 4) is sensitized by PIP and desensitized by Syndapin3/PACSIN3, which bind to the structurally uncharacterized TRPV4 N terminus. We determined the nuclear magnetic resonance structure of the Syndapin3...

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Bibliographic Details
Published inStructure (London) Vol. 26; no. 12; p. 1583
Main Authors Goretzki, Benedikt, Glogowski, Nina A, Diehl, Erika, Duchardt-Ferner, Elke, Hacker, Carolin, Gaudet, Rachelle, Hellmich, Ute A
Format Journal Article
LanguageEnglish
Published United States 04.12.2018
Subjects
SH3 domain
class I
PACSIN
TRP channel
NMR
PIP
TRPV4
Syndapin
cis proline
proline-rich region
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Summary:Transient receptor potential (TRP) channels are polymodally regulated ion channels. TRPV4 (vanilloid 4) is sensitized by PIP 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 PIP binding site. We determined the affinities of the TRPV4 N terminus for PACSIN1, 2, and 3 SH3 domains and PIP and deduce a hierarchical interaction network where Syndapin/PACSIN binding influences the PIP binding site but not vice versa.
ISSN:1878-4186
DOI:10.1016/j.str.2018.08.002