Abstract
The Schlafen family belongs to the interferon-stimulated genes and its members are involved in cell cycle regulation, T cell quiescence, inhibition of viral replication, DNA-repair and tRNA processing. Here, we present the cryo-EM structure of full-length human Schlafen 5 (SLFN5) and the high-resolution crystal structure of the highly conserved N-terminal core domain. We show that the core domain does not resemble an ATPase-like fold and neither binds nor hydrolyzes ATP. SLFN5 binds tRNA as well as single- and double-stranded DNA, suggesting a potential role in transcriptional regulation. Unlike rat Slfn13 or human SLFN11, human SLFN5 did not cleave tRNA. Based on the structure, we identified two residues in proximity to the zinc finger motif that decreased DNA binding when mutated. These results indicate that Schlafen proteins have divergent enzymatic functions and provide a structural platform for future biochemical and genetic studies.
Highlights
The Schlafen (Slfn) family [1,2] belongs to the class of interferon-stimulated genes (ISGs) [3,4]
The tRNA endoribonuclease activity could not be confirmed for human Schlafen 5 (SLFN5), mSlfn1 or mSlfn2 by us and by others [42,78]
Despite performing nuclease activity assays with a variety of nucleic acids, we could not identify a substrate which is cleaved by SLFN5 or mSlfn2
Summary
The Schlafen (Slfn) family [1,2] belongs to the class of interferon-stimulated genes (ISGs) [3,4]. Ten murine and six human Schlafen proteins have been identified, which can be categorized into three subgroups according to their size and domain architecture [1,2,4]. All Schlafen family members share a highly conserved N-terminal core region of approximately 340 amino acids [1,2]. The N-terminal region will be referred to as Schlafen core domain. While subgroup I Schlafen proteins consist of the Schlafen core domain only, subgroups II and III harbor a C-terminal linker domain of unknown function. Subgroup III Schlafen proteins, such as human SLFN5 and SLFN11, possess an additional C-terminal domain with sequence homology to the family of SF1 DNA/RNA helicases [2]. Subgroup I and II members are predominantly located in the cytoplasm, while subgroup III members were mainly detected in the nucleus [28]
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