Deciphering molecular mechanisms of avian magnetoreception by structure predictions and multiscale simulations

• Applicant: Andrei Kostritskii, Ph.D.
• Subject Area: Biophysics ; Animal Physiology and Biochemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 541484920

Magnetoreception is an extraordinary type of sense that allows some animals to feel external magnetic fields. In particular, magnetoreception in form of a magnetic-compass sense allows migratory birds to utilize inclination of the geomagnetic field in their long-distance navigation. The most prominent candidate for a protein to serve as a genuine magnetoreceptor in birds is cryptochrome 4 (Cry4). Expressed in the avian retina, Cry4 absorbs light that triggers an intraprotein electron transfer resulting in a formation of a magnetosensitive radical pair. Whereas the photoinduced radical-pair formation has been well studied in cryptochromes, the mechanism of magnetoreception beyond this very first step remains obscure. In fact, not only does the molecular mechanism of Cry4 transition to an activated signaling conformation remain unclear, but even the activated conformation itself is still to be determined. Moreover, to eventually alter neuronal activity, the photoinduced conformational changes of Cry4 have to propagate further via protein-protein interactions, whose structural details are also largely unknown. The proposed project aims to fill these gaps in the understanding of avian magnetoreception by investigating conformational changes and protein-protein interactions of Cry4 from European robin (ErCry4). To achieve the proposed goal, I will (1) determine the activated conformation of ErCry4, (2) establish a kinetic model of ErCry4 activation, and (3) elucidate mechanisms of signal transduction between ErCry4 and its interaction partners. These objectives will be addressed by means of large-scale protein structure predictions and molecular dynamics simulations at atomistic and coarse-grained resolutions. I will use multiscale simulations in combination with advanced simulation techniques to gain structural and dynamic insights into ErCry4 activation, and I will utilize structure predictions of ErCry4 in complex with its interaction partners to put the molecular model of ErCry4 activation into a broader context of interprotein interactions. As a result, I will propose a molecular mechanism of signal transduction from the magnetosenstivie radical pair through conformational changes of ErCry4 to a change in its protein-protein interactions, thereby adding another piece to the intriguing puzzle of avian magnetoreception.

• DFG Programme: WBP Position