Biochemical functions and structure of Caenorhabditis elegans ZK177.8 protein: Aicardi–Goutières syndrome SAMHD1 dNTPase ortholog

• Authors: Tatsuya Maehigashi, Emory University; Christopher Lim, Yale University; Lydia R. Wade, Emory University; Nicole E. Bowen, Emory University; Kirsten M. Knecht, Yale University; Natalie Alvarez, Emory University; William G Kelly, Emory University; Raymond F Schinazi, Emory University; Dong-Hyun Kim, Kyung-Hee University; Yong Xiong, Yale University; Baek Kim, Emory University
• Journal Title: Journal of Biological Chemistry
• Volume: Volume 299, Number 9
• Publisher: American Society for Biochemistry and Molecular Biology | 2023-08-09, Pages 105148-None
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.jbc.2023.105148
• Subjects: Chemistry, Biochemistry
• Keywords: SAMHD1; dNTPase; structure; C. elegans; ortholog

Abstract

Mutations in sterile alpha motif domain and histidine–aspartate domain–containing protein 1 (SAMHD1) are found in a neurodevelopmental disorder, Aicardi–Goutières syndrome, and cancers, and SAMHD1, which is a deoxynucleoside triphosphate (dNTP) triphosphorylase, was identified as a myeloid-specific HIV-1 restriction factor. Here, we characterized the enzymology and structure of an SAMHD1 ortholog of Caenorhabditis elegans, ZK177.8, which also reportedly induces developmental defects upon gene knockdown. We found ZK177.8 protein is a dNTPase allosterically regulated by dGTP. The active site of ZK177.8 recognizes both 2′ OH and triphosphate moieties of dNTPs but not base moiety. The dGTP activator induces the formation of the enzymatically active ZK177.8 tetramers, and ZK177.8 protein lowers cellular dNTP levels in a human monocytic cell line. Finally, ZK177.8 tetramers display very similar X-ray crystal structure with human and mouse SAMHD1s except that its lack of the canonical sterile alpha motif domain. This striking conservation in structure, function, and allosteric regulatory mechanism for the hydrolysis of the DNA building blocks supports their host developmental roles.