Synapsins I and II are ATP-binding proteins with differential Ca2+ regulation

Synapsins I and II are abundant phosphoproteins that are localized to synaptic vesicles and have essential functions in regulating synaptic vesicle exocytosis, Synapsins contain a single evolutionarily conserved, large central domain, the C-domain, that accounts for the majority of their sequences, Unexpectedly, the crystal structure of the C-domain from synapsin I revealed that it is structurally closely related to several ATPases despite the absence of sequence similarities (Esser, L., Wang, C.-R., Hosaka, M., Smagula, C. S., Sudhof, T. C., and Deisenhofer, J. (1998) EMBO J., in press). We now show that the C-domains of both synapsin I and synapsin II constitute high affinity ATP-binding modules, The two C-domains exhibit similar ATP affinities but are differentially regulated; ATP binding to synapsin I is Ca2+-dependent whereas ATP binding to synapsin II, is Ca2+-independent, In synapsin I, the Ca2+ requirement for ATP binding is mediated by a single, evolutionarily conserved glutamate residue (Glu(373)) at a position where synapsin II contains a lysine residue, Exchange of Glu(373) for lysine converts synapsin I from a Ca2+-dependent protein into a Ca2+-independent ATP-binding protein, Our studies suggest that synapsins I and II function on synaptic vesicles as ATP-binding proteins that are differentially regulated by Ca2+.