9LPK

Structure of human PADI6-UHRF1-UBE2D3 complex

Summary for 9LPK

• Entry DOI: 10.2210/pdb9lpk/pdb
• EMDB information: 63270
• Descriptor: E3 ubiquitin-protein ligase UHRF1, Protein-arginine deiminase type-6, Ubiquitin-conjugating enzyme E2 D3 (3 entities in total)
• Functional Keywords: padi6, uhrf1, ube2d3, ubiquitylation, maternal complex, early embryonic development, ligase/hydrolase, ligase-hydrolase complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 368920.70

Authors

Li, J.,Deng, D. (deposition date: 2025-01-25, release date: 2026-01-28, Last modification date: 2026-04-01)

Primary citation

Li, J.,Lu, Y.,Xia, Z.,Chi, P.,Qi, Q.,Liu, S.,Ju, S.,Li, J.,Zhang, Z.,Han, Z.,Liu, Q.,Meng, W.,Chen, J.,Wang, X.,Guo, L.,Li, L.,Huang, W.,Dai, L.,Han, J.,Gao, S.,Deng, D.
The maternal PADI6-UHRF1-UBE2D complex regulates ubiquitination during oocyte maturation and embryogenesis.
Nat.Struct.Mol.Biol., 33:512-524, 2026

PubMed Abstract: Proteostasis in mammalian oocytes is vital for successful reproduction. The cytoplasmic lattices (CPLs) of oocytes store essential maternal proteins for early embryo development. Here we show that PADI6, a core component of CPLs, forms a conserved ternary complex that we term MPU for maternal PADI6-UHRF1-UBE2D. The MPU complex regulates protein ubiquitination during oocyte maturation and early embryogenesis. We determined the cryo-electron microscopy structure of MPU and show that 86% (25/29) of clinically identified PADI6 missense variants disrupt MPU assembly, revealing a potential molecular mechanism linking dysregulation of ubiquitination on oocytes to abnormal embryonic development. Mechanistically, PADI6, with the assistance of UHRF1, sequesters UBE2D to prevent ubiquitin transfer from E2 to relevant substrate proteins, thereby suppressing the ubiquitination cascade. Therefore, our findings implicate PADI6 in the regulation of proteostasis by controlling the ubiquitination cascade, expanding our understanding of PADI6-dependent regulation of oocyte maturation and early embryogenesis.

PubMed: 41772195
DOI: 10.1038/s41594-026-01758-y

Experimental method

ELECTRON MICROSCOPY (3.03 Å)