Figure 12. Proposed Dyrk1A functions in regulating synaptic vesicle endocytosis.

Dyrk1A phosphorylated AP180 in cytosol. The phosphorylated AP180 may decrease its binding affinity to the AP2 complex; we hypothesize here that the decrease in such binding affinity would reduce recruitment of clathrin at the nucleation and invagination sites. Phosphorylation of dynamin 1, amphiphysin 1, and synaptojanin 1 at their PRD reduces the interaction between the PRDs and the SH3 domains of amphiphysin and endophilin. This likely slows down the invagination and fission steps of synaptic vesicle formation. Once endocytosed, the vesicle-associated proteins are quickly removed from the membranes (uncoating). The Dyrk1A-mediated phosphorylation releases first AP180 and β-adaptin from the vesicle membranes, while both α- and μ-adaptin subunits remain bound with the membranes. Additional factor(s) are required to release the membrane-bound subunits. Clathrin release from the vesicles is independent from Dyrk1A. We speculate that the adaptin subunits released in cytoplasm may reassemble into the AP2 complex after dephosphorylation.