Publication Date
7-1-2025
Journal
Nature Communications
DOI
10.1038/s41467-025-61091-8
PMID
40592880
PMCID
PMC12215978
PubMedCentral® Posted Date
7-1-2025
PubMedCentral® Full Text Version
Post-print
Abstract
The SLFN14 endoribonuclease is a post-transcriptional regulator that targets the ribosome and its associated RNA substrates for codon-bias translational repression. SLFN14 nuclease activity is linked to antiviral defense and platelet function. Despite its prominent role in gene regulation, the molecular signals regulating SLFN14 substrate recognition and catalytic activation remain unclear. SLFN14 dysregulation is linked to human diseases, including ribosomopathies and inherited thrombocytopenia, thus underscoring the importance of establishing the signals coordinating its RNA processing activity. Here, we reconstitute active full-length human SLFN14 and report a high-resolution cryoEM reconstruction of the SLFN14•RNA complex. The structure reveals a medallion-like architecture that shares structural homology with other SLFN family members. We unveil a C-terminal hydrophobic intermolecular interface that stabilizes the SLFN14 homodimer without the need for additional molecular signals. We describe compact sequence-independent RNA binding interfaces and highlight the environment of the SLFN14 disease hotspot at the RNA cleft entrance. We show that the SLFN14 endoribonuclease has broad site-specificity in the absence of modified native tRNA, a characteristic not shared with its SLFN11 family member. Finally, we demonstrate that metal-dependent acceptor stem cleavage requires the SLFN14 E-EhK motif and uncover its unexpected parallel with other virus-activatable nucleases.
Keywords
Humans, Cryoelectron Microscopy, RNA, Endoribonucleases, Protein Binding, Models, Molecular, Enzyme mechanisms, RNA, Cryoelectron microscopy, Hydrolases, Nucleases
Published Open-Access
yes
Recommended Citation
Van Riper, Justin; Martinez-Claros, Arleth O; Wang, Lie; et al., "CryoEM Structure of the SLFN14 Endoribonuclease Reveals Insight Into RNA Binding and Cleavage" (2025). Faculty, Staff and Students Publications. 6553.
https://digitalcommons.library.tmc.edu/baylor_docs/6553