9HMM

Crystal structure of mouse ADAT2/ADAT3 tRNA deamination complex A180V mutant

9HMM の概要

• エントリーDOI: 10.2210/pdb9hmm/pdb
• 分子名称: tRNA-specific adenosine deaminase 2, Probable inactive tRNA-specific adenosine deaminase-like protein 3, ZINC ION, ... (4 entities in total)
• 機能のキーワード: trna modification, wobble adenine, inosine, adat, intellectual disability, neurological disorders, hydrolase
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56168.39

構造登録者

Vaca, H.R.,Romier, C. (登録日: 2024-12-09, 公開日: 2025-05-14, 最終更新日: 2025-09-10)

主引用文献

Del-Pozo-Rodriguez, J.,Tilly, P.,Lecat, R.,Vaca, H.R.,Mosser, L.,Brivio, E.,Balla, T.,Gomes, M.V.,Ramos-Morales, E.,Schwaller, N.,Salinas-Giege, T.,VanNoy, G.,England, E.M.,Kern Lovgren, A.,O'Leary, M.,Chopra, M.,Meave Ojeda, N.,Toosi, M.B.,Eslahi, A.,Alerasool, M.,Mojarrad, M.,Pais, L.S.,Yeh, R.C.,Gable, D.L.,Hashem, M.O.,Abdulwahab, F.,Rakiz Alqurashi, M.,Sbeih, L.Z.,Adas Blanco, O.A.,Khater, R.A.,Oprea, G.,Rad, A.,Alzaidan, H.,Aldhalaan, H.,Tous, E.,Alsagheir, A.,Alowain, M.,Tamim, A.,Alfayez, K.,Alhashem, A.,Alnuzha, A.,Kamel, M.,Al-Awam, B.S.,Elnaggar, W.,Almenabawy, N.,O'Donnell-Luria, A.,Neil, J.E.,Gleeson, J.G.,Walsh, C.A.,Alkuraya, F.S.,AlAbdi, L.,Elkhateeb, N.,Selim, L.,Srivastava, S.,Nedialkova, D.D.,Drouard, L.,Romier, C.,Bayam, E.,Godin, J.D.
ADAT3 variants disrupt the activity of the ADAT tRNA deaminase complex and impair neuronal migration.
Brain, 148:3407-3421, 2025

PubMed Abstract: The ADAT2/ADAT3 (ADAT) complex catalyses the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3, the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders. Yet, the physiological function of the ADAT2/ADAT3 complex during brain development remains totally unknown. Here, we investigated the role of the ADAT2/ADAT3 complex in cortical development. First, we report 21 neurodevelopmental disorders patients carrying biallelic variants in ADAT3. Second, we used structural, biochemical and enzymatic assays to deeply characterize the impact of those variants on the ADAT2/ADAT3 structure, biochemical properties, enzymatic activity, and tRNAs editing and abundance. Finally, in vivo complementation assays were performed to correlate functional deficits with neuronal migration defects in the developing mouse cortex. Our results showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is essential for radial migration of projection neurons in the developing mouse cortex. We demonstrated that the identified ADAT3 variants significantly impaired the abundance and, for some, the activity of the complex, leading to a substantial decrease in inosine 34 levels with direct consequence on tRNAs steady state. We correlated the severity of the migration phenotype with the degree of loss of function caused by the variants. Altogether, our results highlight the critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenic mechanisms underlying ADAT3-related neurodevelopmental disorders.

PubMed: 40120092
DOI: 10.1093/brain/awaf109

実験手法

X-RAY DIFFRACTION (2.9 Å)