Regensburg 2025 – scientific programme

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BP: Fachverband Biologische Physik

BP 30: Protein Structure and Dynamics

BP 30.1: Talk

Thursday, March 20, 2025, 15:00–15:15, H46

A protein sensor for plasma membrane lipid composition – insights from coarse-grained simulations — Saara Lautala and •Sebastian Thallmair — Frankfurt Institute for Advanced Studies, Frankfurt a.M., Germany

Extended synaptotagmins (E-Syts) are tethering proteins, which keep the plasma membrane (PM) and the endoplasmic reticulum (ER) membrane in close proximity at ER-PM contact sites. C2 domains are responsible for the binding of E-Syts to the PM. After depletion of phosphatidylinositol 4,5-bisphosphate PI(4,5)P2, resynthesis of PI(4,5)P2 takes place at ER-PM contact sites and thus, requires their integrity. The terminal C2C domain of E-Syt3 is known to bind PI(4,5)P2. This results in an apparent paradox as the membrane binding and thus the tethered ER-PM contact site potentially become instable upon PI(4,5)P2 depletion.

Here, we applied coarse-grained molecular dynamics simulations with the Martini 3 force field to investigate the membrane binding of the E-Syt3 C2C domain. Our simulations show that the C2C domain not only exhibits a binding hotspot for PI(4,5)P2, but an additional binding hotspot for phosphatidylserine (PS) as well as a region binding to the membrane core. We will discuss that binding to PS results in a reorientation of the protein on the membrane surface and compare the different binding strengths. Overall, the PS binding site not only contributes to the ER-PM contact site integrity upon PI(4,5)P2 depletion, but might also play a role in sensing low PI(4,5)P2 levels.

Keywords: protein-membrane interactions; PIP2; C2 domain; coarse-grained molecular dynamics; Martini 3