Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2
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Glogowski, Nina A.
Hellmich, Ute A.
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CitationGoretzki, Glogowski, Diehl, Duchardt-Ferner, Hacker, Gaudet, and Hellmich. 2018. "Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2." Structure 26 (12): 1583-593.e5.
AbstractTransient 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:38446505
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