Structural Insights into the Intrinsic Self-Assembly of Par-3 N-Terminal Domain

Par-3, the central organizer of the Par-3/Par-6/atypical protein kinase C complex, is a multimodular scaffold protein that is essential for cell polarity establishment and maintenance. The N-terminal domain (NTD) of Par-3 is capable of self-association to form filament-like structures, although the underlying mechanism is poorly understood. Here, we determined the crystal structure of Par-3 NTD and solved the filament structure by cryoelectron microscopy. We found that an intrinsic “front-to-back” interaction mode is important for Par-3 NTD self-association and that both the lateral and longitudinal packing within the filament are mediated by electrostatic interactions. Disruptions of the lateral or longitudinal packing significantly impaired Par-3 NTD self-association and thereby impacted the Par-3-mediated epithelial polarization. We finally demonstrated that a Par-3 NTD-like domain from histidine ammonia-lyase also harbors a similar self-association capacity. This work unequivocally provides the structural basis for Par-3 NTD self-association and characterizes one type of protein domain that can self-assemble via electrostatic interactions. •The structure of Par-3 NTD reveals an intrinsic front-to-back self-association mode•The Par-3 NTD self-assembles into a left-handed helical filament revealed by cryo-EM•Disruptions of the helical packing within the filament impact epithelial polarization•The Par-3 NTD-like domain of HAL also harbors a similar self-association capacity The N-terminal domain (NTD) of Par-3 can self-associate to form a filament-like structure. Zhang et al. determine the crystal structure of Par-3 NTD and reveal an intrinsic “front-to-back” self-association mode. The cryo-EM filament structure further highlights the “left-handed” helical self-assembly of the Par-3 NTD.