9LQ2

Structure of human dimeric NLRP7-TCL1A complex

Summary for 9LQ2

• Entry DOI: 10.2210/pdb9lq2/pdb
• EMDB information: 63291
• Descriptor: Isoform 3 of NACHT, LRR and PYD domains-containing protein 7, T-cell leukemia/lymphoma protein 1A (2 entities in total)
• Functional Keywords: subcortical maternal complex, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 287588.13

Authors

Liu, Q.T.,Li, J.H. (deposition date: 2025-01-27, release date: 2025-12-10, Last modification date: 2026-04-15)

Primary citation

Gao, Z.,Liu, Q.,Li, L.,Hu, T.,Lu, X.,Wu, Y.,Qin, D.,Wang, X.,Gu, C.,Li, J.,Xu, C.,Zhou, D.,Zhou, F.,Bai, Y.,Kang, X.,Liu, J.,Deng, D.,Li, L.
TCL1A mediates DNA methylation defects in recurrent hydatidiform mole with NLRP7 pathogenic variants.
Nat Commun, 17:-, 2026

PubMed Abstract: Pathogenic variants in NLRP7, implicated in 55% of recurrent hydatidiform mole characterized by hypomethylation at maternally methylated imprinted regions, are proposed to disrupt de novo DNA methylation in human oocytes. However, the precise mechanism remains unclear. Here, we identify TCL1A, a DNMT3A inhibitor, as an endogenous NLRP7-interacting partner. The cryo-EM structure of the NLRP7-TCL1A complex reveals its fundamental architecture. Comprehensive analysis demonstrates that the majority of recurrent hydatidiform mole-causing NLRP7 variants impair its interaction with TCL1A. Mechanistically, NLRP7 potentially safeguards oocyte methylome by sequestering TCL1A in the cytoplasm, thereby preventing its nuclear entry and subsequent suppression of DNMT3A-mediated de novo methylation. Combining in silico predictions and interaction analysis, we identify L766R as a pathogenic variant. These findings propose a cytoplasmic regulatory mechanism governing nuclear DNA methylation, explaining the hypomethylation pathogenesis in NLRP7 variant-associated recurrent hydatidiform mole.

PubMed: 41786744
DOI: 10.1038/s41467-026-69744-y

Experimental method

ELECTRON MICROSCOPY (3.58 Å)