Synaptic adhesion molecules (SAMs) are essential for driving the formation, maturation, and plasticity of synaptic connections for neural networks. MAM domain-containing glycosylphosphatidylinositol anchors (MDGAs) are a type of SAM that regulates the formation oftrans-synaptic bridges, which are critical for neurotransmission and synaptic differentiation. In a recent issue of the JBC, Leeet al.uncovered that MDGA1 can control protein–protein interactions and synaptic cleft activity by adopting different global 3D conformations. This novel molecular mechanism may be applicable to other SAMs that regulate protein–protein interactions and nanoscale organization in the synaptic cleft.