Multilayered regulatory networks in the intrinsically disordered regions of TRP ion channels

Datum

01.10.2024

Zeit

10:00 - 11:00

Sprecher

Ute A. Hellmich

Zugehörigkeit

Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena

Sprache

en

Hauptthema

Biologie

Host

André Nadler

Beschreibung

Intrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. The members of the Transient Receptor Potential (TRP) channel superfamily of ion channels are characterized by large N- and C-terminal IDRs that mediate intra- and intermolecular contacts with other proteins and the lipid bilayer1. TRP channels play central roles in almost every (patho)physiological process, including thermo- and osmosensation, nociception and infectious diseases2. A molecular understanding of the polymodality of TRP channel regulation is thus crucial for a fundamental understanding of sensory perception and cellular responses to diverse stimuli. We hypothesize that the IDRs harbor regulatory elements that allow TRP channels to meaningfully integrate diverse signaling inputs. We recently generated the first full-length structural model of a TRP channel, TRP Vanilloid 4, that takes the dimensions of the IDR and its membrane-interactions into account3. Intriguingly, deletion of the channel’s N-terminal IDR, consisting of ~150 amino acids, renders TRPV4 unresponsive to osmotic stimuli, while distinct IDR regions enhance or subdue channel function. Together, these regulatory elements in the IDR modulate channel responses in a hierarchical, lipid-dependent manner. To enhance our understanding of TRP channel regulation by its large IDR, we also incorporated small molecules, proteins and disease mutations4 into our functional model of TRPV4. Furthermore, by exploring the structural dynamics and functional roles of the IDRs in other TRP channels, we find that multilayered signal integration by the IDRs is a widespread phenomenon in this important protein family. Accordingly, to understand TRP channel function, their often extensive IDRs cannot be ignored. Our work shows that “IDR cartography”, i.e., mapping structural and functional properties onto distinct IDR regions through an integrated structural biology approach, sheds light on the complex regulation of membrane receptors through their hitherto mostly neglected regions and provides a framework for signal integration on the molecular level.

Letztmalig verändert: 01.10.2024, 07:40:26