Phosphorylation regulates BICD2 and the function of the dynein motor complex in G2/M

Trabajo presentado en la XXVIII Jornada de Biología Molecular, celebrada en Barcelona (España) el 04 de noviembre de 2022.The dynein complex is the major microtubule minus-end-directed motor of the cell. As so, it is involved in the intracellular movement of a plethora of cellular organelles and structures, such as different types of vesicles, RNA particles, protein complexes and aggregates as well as viruses. It is also key for the correct organization, positioning and function of the mitotic spindle during mitosis and it controls nuclear positioning and movement during cell migration as well as the specialized nuclear movements that take place in neural progenitors during the development of the brain cortex. Dynein is essential in most organisms, and mutations in its components lead to several developmental and neurodegenerative disorders in humans. The activity of dynein is regulated by a number of adaptors that mediate its interaction with the functionally related dynactin complex, effectively activating the motor while also connecting it to different cargos. The regulation of adaptors is consequently central to dynein physiology, but remains largely unexplored. We now describe that one of the best-known dynein adaptors, BICD2, is effectively activated through phosphorylation. In the G2 phase of the cell cycle, phosphorylation of BICD2 by CDKs promotes its interaction with the Polo-like kinase PLK1. In turn, PLK1 phosphorylates a single residue in the N-terminus of BICD2 resulting in a conformational change that facilitates interaction with dynein and dynactin, and allows the formation of an active motor complex. We show that BICD2 phosphorylation is central for dynein recruitment to the nuclear envelope, centrosome tethering to the nucleus and centrosome separation in G2/M. Our work reveals adaptor activation through phosphorylation as crucial for the spatiotemporal regulation of dynein activity