Journal Article

PUBDB-2023-06835

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity

Goretzki, B.Extern*EMBL* ; Wiedemann, C.Extern*EMBL* ; McCray, B. A. ; Schäfer, S. L. ; Jansen, J. ; Tebbe, F.Extern*EMBL* ; Mitrovic, S.-A.Extern*EMBL* ; Nöth, J.Extern*EMBL* ; Cabezudo, A. C. ; Donohue, J. K. ; Jeffries, C.EMBL* ; Steinchen, W. ; Stengel, F. ; Sumner, C. J. ; Hummer, G. ; Hellmich, U. A. (Corresponding author)Extern*EMBL*

2023
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-023-39808-4  doi:10.3204/PUBDB-2023-06835

Abstract: Intrinsically 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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Contributing Institute(s):

1. EMBL (EMBL)
2. EMBL-User (EMBL-User)
3. DOOR-User (DOOR ; HAS-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project 390713860 - EXC 2051: Balance of the Microverse (390713860) (390713860)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2023

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