Liu, Y.; Wang, X.; Zheng, T.; Niu, F.; Sun, R.; Yang, C.; Xu, S.; Zhao, Z.; Shen, Z.; Huang, W.; Wang, X.; Liu, K.; Cai, S.; Zhang, M.; Wei, Z.

Mesoscale molecular apparatuses with diverse functions are widespread in cells. How mesoscale cellular apparatuses are formed and regulated is poorly understood. The synaptic ribbon in sensory neurons, which can dynamically adjust its size and shape in response to light or sound, is a mesoscale molecular assembly. In this study, we demonstrate that RIBEYE, the backbone protein of synaptic ribbons, via combined ordered and disordered interactions, forms micron-sized dynamic molecular assemblies. Integrated cryo-electron microscopy and tomography studies revealed that the N-terminal SAM domain and the C-terminal B domain of RIBEYE form distinct nanoscale filaments and further assemble into ribbon-like architectures via phase transition. Unexpectedly, the N-terminal intrinsically disordered region of RIBEYE softens the solid mesoscale ribbon structures via phase separation. The mesoscale size and shape of the RIBEYE condensate are bidirectionally tuned by physiological modulators such as Piccolino and CtBP1, linking synaptic ribbon structural plasticity to functional adaptability. Thus, our study demonstrates that combined phase transition and phase separation of nanoscale protein oligomers can build mesoscale functional cellular apparatuses.