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BP: Fachverband Biologische Physik

BP 31: Protein Structure and Dynamics

BP 31.10: Vortrag

Donnerstag, 21. März 2024, 17:45–18:00, H 0112

IP3 affinity of Tubby reveals cooperativity mechanism for membrane binding — •Sebastian Thallmair — Frankfurt Institute for Advanced Studies (FIAS), Germany

We recently showed by means of coarse-grained (CG) molecular dynamics (MD) simulations and life cell experiments that two cooperative binding sites of the C-terminal domain of the Tubby protein determine its PI(4,5)P2 affinity. Notably, the PI(4,5)P2 concentration sensitivity of the Tubby protein is more pronounced than the one of the well-known PI(4,5)P2 binding Pleckstrin homology (PH) domain of phospholipase C (PLC)-δ1.

Here, I will show that surprisingly the IP3 affinity of Tubby is comparably to the one of the PLCδ1-PH domain using CG MD simulations with the Martini 3 force field. This is in contrast to the pronounced affinity difference between both proteins to a single PI(4,5)P2 lipid embedded in a POPC membrane. In addition, I will compare both affinities to a single PI(4,5)P2 lipid in water. Taken together, my results indicate that the recently discovered second PI(4,5)P2 binding site of Tubby not only preferably interacts with PI(4,5)P2, but also disfavors the interaction with zwitterionic lipids such as POPC. I will discuss how this increases the PI(4,5)P2 concentration sensitivity of Tubby compared to the PLCδ1-PH domain.

Keywords: peripheral membrane protein; PI(4,5)P2; cooperativity; PH domain; coarse-grained molecular dynamics