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  3. Structural analysis of ASCH domain-containing proteins and their implications for nucleotide processing

Structural analysis of ASCH domain-containing proteins and their implications for nucleotide processing

  • Structure. 2025 Sep 3:S0969-2126(25)00319-3. doi: 10.1016/j.str.2025.08.015.
Chunyan Meng 1,  Xiaoyan Shi 2,  Wenting Guo 3,  Xing Jian 1,  Jie Zhao 4,  Yan Wen 3,  Ruiqi Wang 2,  Yu Li 4,  Sha Xu 5,  Haitao Chen 6,  Jiayu Zhang 7,  Mingjia Chen 8,  Hao Chen 9,  Baixing Wu 10
Affiliations

Affiliations

  • 1 China-New Zealand Joint Laboratory on Biomedicine and Health, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China.
  • 2 Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong & Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen 518055, China.
  • 3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
  • 4 College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China.
  • 5 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
  • 6 School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China.
  • 7 China-New Zealand Joint Laboratory on Biomedicine and Health, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China. Electronic address: zhangjy226@mail2.sysu.edu.cn.
  • 8 College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China. Electronic address: mjchen@njau.edu.cn.
  • 9 Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong & Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen 518055, China. Electronic address: chenh7@sustech.edu.cn.
  • 10 China-New Zealand Joint Laboratory on Biomedicine and Health, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China. Electronic address: wu_baixing@gibh.ac.cn.
PMID: 40939588 DOI: 10.1016/j.str.2025.08.015
Abstract

ASC-1 homology (ASCH) domain family proteins are believed to play essential roles in RNA metabolism, but detailed structural and functional information is limited. Research has shown that the E. coli enzyme YqfB, which contains an ASCH domain, has amidohydrolase activity, converting N4-acetylcytidine (ac4C) RNA nucleoside into cytidine. Here, we present the crystal structures of EcYqfB both in its unbound state and bound to a substrate. Our analysis reveals how the substrate interacts with the enzyme, offering insights into its catalytic mechanism. In vivo experiments further show that deleting EcYqfB does not change overall ac4C levels across various RNA types, indicating that EcYqfB specifically functions in ac4C nucleoside metabolism. We also determined the structures of two homologous proteins: mouse EOLA1 and the human TRIP4-ASCH domain, highlighting differences in their substrate preferences. These findings offer important insights for future research into the structure and function of the ASCH domain protein family.

Keywords

ASCH domain; Crystal structure; RNA modification; ac(4)C; amidohydrolase.

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