Zinc mediates the allosteric activation of Shiftless to suppress programmed -1 ribosomal frameshifting.

Authors

Shi-Ting He, Yongfeng Zheng, Ruhong Ying, Xu Xu, Qiman Fang, Xiujuan Li, Runxi Luo, Xinqi Zhu, Yumin Huang, Yuzheng Zhou, Xiaonan Dong

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 40. Pages e2608087123. Oct 06, 2026. Epub Sep 28, 2026.

Abstract

Many medically important viruses, including HIV-1 and severe acute respiratory syndrome coronavirus 2, utilize programmed -1 ribosomal frameshifting (-1 PRF) to synthesize certain proteins essential for the viral life cycle. Shiftless (SHFL) is an interferon-simulated, zinc finger-containing protein that restricts -1 PRF and viral infection. However, its regulatory spectrum and mechanism remain largely unclear. Here, we showed that SHFL orthologs potently suppress a wide variety of viral and cellular -1 PRF, and that this activity is evolutionarily conserved in mammals. Notably, mammalian SHFL proteins contain three zinc finger domains and inhibit -1 PRF in a zinc ion- and zinc finger-dependent manner. Structural and biochemical analyses revealed that SHFL is an autoinhibited protein, in which the C-terminal domain (CTD) serves as the principal functional module through mediating RNA binding, homotypic oligomerization, and ribosomal interaction, whereas the N-terminal domain (NTD) negatively regulates CTD activity through intramolecular interaction. Either zinc binding to the three zinc fingers or genetical disruption of the NTD-CTD interaction by point mutagenesis likely drives conformational rearrangement that relieves autoinhibition and converts SHFL into an active conformation. Together, these findings uncover a previously unrecognized mechanism of zinc ion- and zinc finger-mediated allosteric activation of SHFL, providing a molecular framework for broad-spectrum suppression of viral and cellular -1 PRF.

PMID:
42804643
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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