Oligomeric Plasticity Gating Mechanisms in Ion Channels

Projektbeschreibung

Verborgene Dynamiken in Ionenkanälen aufdecken

Ionenkanäle sind Proteine. Sie steuern den Ionenfluss durch die Zellmembranen und sind für viele körperliche Funktionen und Erkrankungen unerlässlich. Erkenntnisse über ihr Verhalten sind wichtig für die Entwicklung gezielt wirkender Medikamente. Ihre seltenen, kurzlebigen Hochenergiezustände sind jedoch weitgehend unerforscht. Das ERC-finanzierte Projekt OLIGOMERS untersucht diese flüchtigen Zustände mittels Hochgeschwindigkeits-Atomkraftmikroskopie (HS-AFM. Erste Ergebnisse deuten auf einen seltenen pentameren Zustand im TRPV3-Kanal hin, der reversibel mit seiner normalen tetrameren Form interagiert. Nun wird erforscht, ob ähnliche Übergänge auch in anderen Ionenkanälen auftreten. OLIGOMERS wird ihre funktionellen Auswirkungen und biologische Bedeutung prüfen. Die Ergebnisse werden neue Wege für die Arzneimittelentwicklung eröffnen.

Ziel

Ion channels are transmembrane proteins regulating ion flux across cell membranes and are crucial for numerous physiological processes. Hence, ion channels are implicated in many diseases. To further drug development targeting ion channels, a comprehensive understanding is needed not only of their low-energy abundant states, but also of their rare and transient high-energy states, which play critical roles in channel function, regulation, and folding. The cutting-edge high-speed atomic force microscopy (HS-AFM) technique allows now to study such states, by providing simultaneously, on a single-molecule level, both dynamic and structural information of freely diffusing ion channels in the membrane, a feat that is currently impossible with other methods. Recently, I discovered using HS-AFM that the TRPV3 channel possesses a rare and transient pentameric state that reversibly interconverts with its canonical tetrameric sate, potentially conferring it new function. Here, I aim to investigate further the functional role and biological relevance of this finding, while concomitantly investigating if similar oligomeric plasticity occurs in other ion channels of diverse functions. Most particularly, I aim to investigate whether reversible oligomeric changes could be an additional mechanism for ion channels to modulate function. To do so, I will: 1) Discover reversible oligomeric transitions in other ion channels. 2) Reveal how reversible oligomeric transitions could modulate function. 3) Assess the physiological relevance and feasibility of such transitions. Positive results will lead to a paradigm shift in the way we think about the assembly, dynamics, and function of ion channels and introduce a novel new concept of how ion channels undergo conformational changes. Additionally, results will be of high impact to translational applications such as drug development and drug delivery and establish HS-AFM as a powerful complementary method in the field of structural biology.