Molecular basis of PADI6 species-specific oligomerization in maternal regulatory complexes

Abstract

Peptidyl arginine deiminase 6 (PADI6) is an essential maternal effector in mammalian oocytes and preimplantation embryos. Recently, we identified the conserved maternal PADI6-UHRF1-UBE2D complex (MPU). MPU, together with the subcortical maternal complex (SCMC), further forms the cytoplasmic lattices (CPLs). Here, we reconstitute the mouse MPU (mMPU) and uncover striking species-specific differences in PADI6 oligomerization. In solution, mouse PADI6 (mPADI6) undergoes further oligomerization, forming tetramers, higher-order oligomers, and filamentous assemblies. Cryo-EM analysis reveals that the N-terminal IgG domain of mPADI6 mediates this behavior. These distinct oligomerization properties alter the stoichiometric ratios of the three components during assembly of both human MPU and mMPU. Moreover, PADI6 from different species adopts distinct oligomeric states in solution, suggesting potential differences in CPL assembly mechanisms. Together, our findings define the differential oligomerization capacity of PADI6 at the molecular level and provide a critical framework for understanding PADI6-mediated maternal regulatory assemblies during early embryonic development in different species. Maternal effector PADI6 forms the MPU complex with UHRF1 and UBE2D and assembles CPLs with SCMC members in oocytes and early embryos. PADI6’s oligomerization capacity, driven by its N-terminal domain, defines species-specific MPU structure and highlights differences in CPL architecture and regulatory mechanisms