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000598500 1001_ $$0P:(DE-H253)PIP1090124$$aGoretzki, Benedikt$$b0
000598500 245__ $$aCrosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity
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000598500 520__ $$aIntrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. TRPV4, a member of the TRP vanilloid channel family involved in thermo- and osmosensation, has a large N-terminal IDR of approximately 150 amino acids. With an integrated structural biology approach, we analyze the structural ensemble of the TRPV4 IDR and the network of antagonistic regulatory elements it encodes. These modulate channel activity in a hierarchical lipid-dependent manner through transient long-range interactions. A highly conserved autoinhibitory patch acts as a master regulator by competing with PIP2 binding to attenuate channel activity. Molecular dynamics simulations show that loss of the interaction between the PIP2-binding site and the membrane reduces the force exerted by the IDR on the structured core of TRPV4. This work demonstrates that IDR structural dynamics are coupled to TRPV4 activity and highlights the importance of IDRs for TRP channel function and regulation.
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000598500 7001_ $$0P:(DE-H253)PIP1100673$$aWiedemann, Christoph$$b1
000598500 7001_ $$00000-0001-6581-9728$$aMcCray, Brett A.$$b2
000598500 7001_ $$0P:(DE-HGF)0$$aSchäfer, Stefan L.$$b3
000598500 7001_ $$aJansen, Jasmin$$b4
000598500 7001_ $$0P:(DE-H253)PIP1092900$$aTebbe, Frederike$$b5
000598500 7001_ $$0P:(DE-H253)PIP1090123$$aMitrovic, Sarah-Ana$$b6
000598500 7001_ $$0P:(DE-H253)PIP1090122$$aNöth, Julia$$b7
000598500 7001_ $$00000-0003-1400-4929$$aCabezudo, Ainara Claveras$$b8
000598500 7001_ $$aDonohue, Jack K.$$b9
000598500 7001_ $$0P:(DE-H253)PIP1018937$$aJeffries, Cy$$b10
000598500 7001_ $$aSteinchen, Wieland$$b11
000598500 7001_ $$00000-0003-1447-4509$$aStengel, Florian$$b12
000598500 7001_ $$00000-0001-5088-6012$$aSumner, Charlotte J.$$b13
000598500 7001_ $$00000-0001-7768-746X$$aHummer, Gerhard$$b14
000598500 7001_ $$0P:(DE-H253)PIP1100686$$aHellmich, Ute A.$$b15$$eCorresponding author
000598500 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-023-39808-4$$gVol. 14, no. 1, p. 4165$$n1$$p4165$$tNature Communications$$v14$$x2041-1723$$y2023
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