Berlin University Alliance

Cellular localization and three-dimensional structures of ATM-Drebrin-actin functional complexes in neurons

Researcher: Dr. Magdalena Schacherl, Charité – Universitätsmedizin Berlin, Institute of Medical Physics and Biophysics

Measuring facility: CFcryoEM: Core Facility for Cryo Electron Microscopy (Charité)

The brain controls and coordinates our actions by transmitting signals to and from different parts of our body. The main cell population involved in this signal transmission constitute neurons, which communicate via synapses. Synaptic transmission requires a high amount of glucose and oxygen to support ATP demands and consequently produces a robust amount of reactive oxygen species. It has recently been shown that the actin binding protein Drebrin coordinates an excess of reactive oxygen species with cytoskeletal dynamics via a mechanism involving the kinase ataxia-telangiectasia mutated (ATM) to safeguard synapse integrity (1,2).

Using cryo-electron microscopy within the cell (cryo-electron tomography), we are studying at the synapse, where ATM and Drebrin are located, how they are organized and what happens to them upon stress induction. We are also interested in their interaction with the cytoskeletal protein filamentous actin (F-actin). To obtain atomic-level information of the structure of all three proteins, we are studying them in isolation using single-particle analysis. Altogether, we hope to get insights into the molecular functions of these proteins in the native context of neurons to understand, how they contribute to improved stress resilience at the synapse.

1. Pizzamiglio, L., Focchi, E. & Antonucci, F. ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry. Cells 9, (2020).

2. Kreis, P. et al. ATM phosphorylation of the actin-binding protein drebrin controls oxidation stress-resistance in mammalian neurons and C. elegans. Nat. Commun. 10, 486 (2019).