6533b828fe1ef96bd1287795

RESEARCH PRODUCT

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

Erika DiehlErika DiehlUte A. HellmichUte A. HellmichRachelle GaudetNina A. GlogowskiNina A. GlogowskiCarolin HackerBenedikt GoretzkiBenedikt GoretzkiElke Duchardt-ferner

subject

0301 basic medicineChemistryAffinitiesSH3 domainN-terminus03 medical and health sciencesTransient receptor potential channel030104 developmental biologyStructural biologyStructural BiologyHelixBiophysicslipids (amino acids peptides and proteins)Molecular BiologyIon channelPolyproline helix

description

Summary Transient receptor potential (TRP) channels are polymodally 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.

yearjournalcountryeditionlanguage
2018-12-01Structure
https://doi.org/10.1016/j.str.2018.08.002