SKM 2021 – wissenschaftliches Programm

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BP: Fachverband Biologische Physik

BP 2: Cytoskeleton

BP 2.2: Vortrag

Montag, 27. September 2021, 12:00–12:15, H1

A novel second PI(4,5)P₂ binding site determines PI(4,5)P₂ sensitivity of the tubby domain — Veronika Thallmair¹, Lea Schultz¹, Wencai Zhao¹, Siewert J. Marrink², Dominik Oliver¹, and •Sebastian Thallmair^2,3 — ¹Philipps-University Marburg, Germany — ²University of Groningen, The Netherlands — ³Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany

Phosphoinositides (PIs) are important signaling lipids multitasking in diverse cellular signaling pathways. They operate by recruiting proteins to the membrane surface by means of PI recognition domains. One of the recognition domains for PI(4,5)P₂ lipids, which is the major PI species in the plasma membrane, is the tubby domain. It is conserved in the tubby-like protein (TULP) family and plays an important role in targeting proteins into cilia.

We used coarse-grained (CG) molecular dynamics (MD) simulations with the re-parametrized Martini 3 force field to explore the PI(4,5)P₂ affinity of the C-terminal tubby domain (tubbyCT). Our CG MD simulations revealed a novel second binding site consisting of a conserved cationic cluster at the protein-membrane interface. The simulations together with mutation experiments in living cells showed that the second binding site substantially contributes to the fine-tuned PI(4,5)P₂ affinity of tubbyCT. We will discuss the computational and experimental characterization of the novel binding site, its importance for the membrane targeting properties of tubbyCT, and for its ability to recognize distinct PI(4,5)P₂ pools in the plasma membrane.