Structural and functional characterization of human SLFN14

The Schlafen (SLFN) family of proteins are a group of DNA/RNA processing enzymes with emerging importance in human health and disease, where their functions are implicated in a variety of immunological and anti-tumor processes. Here, we present the cryo-electron microscopy structure of full-length human SLFN14, a member with antiviral activity and linked to an inherited bleeding disorder. SLFN14 is composed of an RNase domain, a SWADL domain, and a two-lobe helicase domain. SLFN14 exhibited strong RNase activity over different substrates, and the positively charged patches at the valley of the RNase domain, which contains the thrombocytopenia-related missense mutation sites, are crucial for binding oligonucleotides. SLFN14 lacks helicase activity, which can be attributed to the inability to bind ATP and the absence of positive charges at the canonical DNA-binding site of its RecA-like folds. SLFN14 is structurally similar to SLFN11, but differs from SLFN5 in the orientation of the helicase domain. Live-cell fluorescence resonance energy transfer (FRET) assays and AlphaFold2 analysis hinted that SLFN14 may adopt multiple conformations in cells. These results provide detailed structural and biochemical features of SLFN14, and greatly expand our knowledge of the functional diversity of the SLFN family.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-05-22
DOI
https://doi.org/10.1093/nar/gkaf484
Citations
2
Primary Topic
PARP inhibition in cancer therapy
Type
article
Field-Weighted Citation Impact
2.09

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article

Structural and functional characterization of human SLFN14

Neil V. Morgan, Song Gao, Sheng Wang, Jiazhen Chen et al.
2 citations
Nucleic Acids Research
PARP inhibition in cancer therapy
2.09
article

Structural and functional characterization of human SLFN14

Neil V. Morgan, Song Gao, Sheng Wang, Jiazhen Chen, Wen Wang, Bing Yu, Kai Deng, Lin Huang, Jun-Ying Ou, Tongsheng Chen, Xudong Jia, Jun Yang, Ziwen Wang, Qinfen Zhang, Meng Luo, Jian-Xiong Feng
article en
2 citations

Abstract

The Schlafen (SLFN) family of proteins are a group of DNA/RNA processing enzymes with emerging importance in human health and disease, where their functions are implicated in a variety of immunological and anti-tumor processes. Here, we present the cryo-electron microscopy structure of full-length human SLFN14, a member with antiviral activity and linked to an inherited bleeding disorder. SLFN14 is composed of an RNase domain, a SWADL domain, and a two-lobe helicase domain. SLFN14 exhibited strong RNase activity over different substrates, and the positively charged patches at the valley of the RNase domain, which contains the thrombocytopenia-related missense mutation sites, are crucial for binding oligonucleotides. SLFN14 lacks helicase activity, which can be attributed to the inability to bind ATP and the absence of positive charges at the canonical DNA-binding site of its RecA-like folds. SLFN14 is structurally similar to SLFN11, but differs from SLFN5 in the orientation of the helicase domain. Live-cell fluorescence resonance energy transfer (FRET) assays and AlphaFold2 analysis hinted that SLFN14 may adopt multiple conformations in cells. These results provide detailed structural and biochemical features of SLFN14, and greatly expand our knowledge of the functional diversity of the SLFN family.

Nucleic Acids ResearchVol. 53(10)
Sun Yat-sen University (CN), South China Normal University (CN), Biocon (Switzerland) (CH), Sun Yat-sen Memorial Hospital (CN), Institute of Human Virology (NG), Sun Yat-sen University Cancer Center (CN), Viva Biotech (China) (CN), University of Birmingham (GB)
British Heart Foundation, National Natural Science Foundation of China, Sun Yat-sen University, Natural Science Foundation of Guangdong Province, Sun Yat-sen University Cancer Center
Affordable and clean energy
Openalex Percentile: Top 12%
PARP inhibition in cancer therapy
2.09
DOIOpen Access PDFOpenAlex
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