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Structure. 2018 Dec 4;26(12):1583-1593.e5. doi: 10.1016/j.str.2018.08.002. Epub 2018 Sep 20.

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

Author information

1
Institute for Pharmacy and Biochemistry, Johannes Gutenberg-Universität Mainz, 55128 Mainz, Germany; Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-Universität, 60438 Frankfurt am Main, Germany.
2
Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-Universität, 60438 Frankfurt am Main, Germany; Institute for Molecular Biosciences, Goethe-Universität, 60438 Frankfurt am Main, Germany.
3
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
4
Institute for Pharmacy and Biochemistry, Johannes Gutenberg-Universität Mainz, 55128 Mainz, Germany; Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-Universität, 60438 Frankfurt am Main, Germany. Electronic address: u.hellmich@uni-mainz.de.

Abstract

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.

KEYWORDS:

NMR; PACSIN; PIP(2); SH3 domain; Syndapin; TRP channel; TRPV4; cis proline; class I; proline-rich region

PMID:
30244966
PMCID:
PMC6281781
[Available on 2019-12-04]
DOI:
10.1016/j.str.2018.08.002

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