9WVI

Crystal structure of TONSL UBL mutant - R934W

Summary for 9WVI

• Entry DOI: 10.2210/pdb9wvi/pdb
• Descriptor: Tonsoku-like protein (2 entities in total)
• Functional Keywords: tonsl, sponastrime dysplasia, mutation, oligomerisation, dna repair, chaperone
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 39200.03

Authors

Karmakar, A.,Roy, S. (deposition date: 2025-09-20, release date: 2025-10-08, Last modification date: 2026-08-12)

Primary citation

Karmakar, A.,Roy, S.
Pathogenic variants in the human TONSL protein associated with SPONASTRIME dysplasia impair protein dimerization and DNA repair.
Sci Adv, 12:eaee1129-eaee1129, 2026

PubMed Abstract: TONSL safeguards genome stability by facilitating replication-dependent DNA damage repair and protecting stalled replication forks through homologous recombination. Mutations in TONSL cause SPONASTRIME dysplasia, a rare skeletal disorder. We reveal that TONSL homo-dimerizes via its ubiquitin-like domain (UBL), and two recurrent SPONASTRIME dysplasia causative variants (R934W and G973R) abolish this dimerization. Crystal structures at 1.9 Å resolution show UBL forms domain-swapped dimers that assemble into ring-like octamers. The R934W variant eliminates critical hydrogen bonds and introduces steric clashes, forcing monomeric conformation. G973R destabilizes an evolutionarily conserved residue within a conformationally restricted β-turn. Biochemically, UBL exists as dimers while UBL remains monomeric. Functionally, dimerization-deficient variants fail to suppress replication stress-induced DNA damage, show impaired RAD51 foci formation, and exhibit severely compromised survival following genotoxic stress. These findings establish TONSL dimerization as essential for genome maintenance and provide structural and mechanistic insights into SPONASTRIME dysplasia pathogenesis.

PubMed: 42525765
DOI: 10.1126/sciadv.aee1129

Experimental method

X-RAY DIFFRACTION (2.19 Å)