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Members of the F-box protein family, such as Scrapper, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1, cullin, and F-box proteins, act as protein-ubiquitin ligases. Scrapper is selectively expressed in the brain, broadly expressed within the mouse CNS and is abundant at presynaptic membrane. Scrapper has orthologs in C. elegans, D. melanogaster, and mammals which suggests that it might function as an important membrane-localized E3 ligase in various species. Scrapper is a major presynaptic E3 ubiquitin ligase that acts through RIM1a via degradation and the ubiquitin-proteasome-system (UPS) pathway to critically regulate synaptic transmission. This identifies protein degradation as a mechanism for holding synaptic communication in check.