mSYD1A, a Mammalian Synapse-Defective-1 Protein, Regulates Synaptogenic Signaling and Vesicle Docking

•Identification of mammalian Synapse-defective-1 orthologs•Loss of mammalian SYD1A impairs synaptic vesicle docking and transmission•mSYD1A assembles into complexes with LAR, liprin-α2 and Munc18-1•mSYD1A presynaptic function relies on an intrinsically disordered domain

SummaryStructure and function of presynaptic terminals are critical for the transmission and processing of neuronal signals. Trans-synaptic signaling systems instruct the differentiation and function of presynaptic release sites, but their downstream mediators are only beginning to be understood. Here, we identify the intracellular mSYD1A (mouse Synapse-Defective-1A) as a regulator of presynaptic function in mice. mSYD1A forms a complex with presynaptic receptor tyrosine phosphatases and controls tethering of synaptic vesicles at synapses. mSYD1A function relies on an intrinsically disordered domain that interacts with multiple structurally unrelated binding partners, including the active zone protein liprin-α2 and nsec1/munc18-1. In mSYD1A knockout mice, synapses assemble in normal numbers but there is a significant reduction in synaptic vesicle docking at the active zone and an impairment of synaptic transmission. Thus, mSYD1A is a regulator of presynaptic release sites at central synapses.