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.

中文翻译：

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TRPV4 N总站与Syndapin / PACSIN1-3和PIP2相互作用的结构基础。

瞬态受体电位（TRP）通道是多峰调节的离子通道。TRPV4（香草素4）通过PIP ₂增感，并通过Syndapin3 / PACSIN3脱敏，Syndapin3 / PACSIN3与结构上未表征的TRPV4 N末端结合。我们确定了Syndapin3 / PACSIN3 SH3域与TRPV4 N末端脯氨酸富集区（PRR）结合的核磁共振结构，该区域结合为I类聚脯氨酸II（PPII）螺旋。该PPII构象被保守的脯氨酸以顺式构象破坏。除PPII外，我们发现近端TRPV4 N总站是非结构化的，这一特征在整个物种中都是保守的，因此可以解释在先前的结构研究中解决它的困难。Syndapin / PACSIN SH3域结合导致PRR和相邻PIP _2的刚性化结合位点。我们确定了TRPV4 N末端对PACSIN1、2和3 SH3域和PIP ₂的亲和力，并推导了一个层次相互作用网络，其中Syndapin / PACSIN结合会影响PIP ₂结合位点，反之则不然。