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

Tatsuya Maehigashi; Christopher Lim; Lydia R Wade; Nicole E Bowen; Kirsten M Knecht; Natalie N Alvarez; William G Kelly; Raymond F Schinazi; Dong-Hyun Kim; Yong Xiong; Baek Kim

doi:10.1016/j.jbc.2023.105148

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

J Biol Chem. 2023 Sep;299(9):105148. doi: 10.1016/j.jbc.2023.105148. Epub 2023 Aug 9.

Authors

Affiliations

¹ Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA.
² Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.
³ Department of Biology, Emory University, Atlanta, Georgia, USA.
⁴ Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA; Center for ViroScience and Cure, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
⁵ Neurobiota Research Center, College of Pharmacy, Kyung-Hee University, Seoul, South Korea.
⁶ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA. Electronic address: yong.xiong@yale.edu.
⁷ Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA; Center for ViroScience and Cure, Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Electronic address: baek.kim@emory.edu.

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.

Keywords: C. elegans; SAMHD1; dNTPase; ortholog; structure.

Abstract

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