The zinc fingers of the SR-like protein ZRANB2 are single-stranded RNA-binding domains that recognize 5' splice site-like sequences

Fionna E. Loughlin, Robyn E Mansfield, Paula M. Vaz, Aaron P. McGrath, Surya Setiyaputra, Roland Gamsjaeger, Eva S. Chen, Brian J Morris, J Mitchell Guss, Joel P Mackay

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64 Citations (Scopus)


The alternative splicing of mRNA is a critical process in higher eukaryotes that generates substantial proteomic diversity. Many of the proteins that are essential to this process contain arginine/serine-rich (RS) domains. ZRANB2 is a widely-expressed and highly-conserved RS-domain protein that can regulate alternative splicing but lacks canonical RNA-binding domains. Instead, it contains 2 RanBP2-type zinc finger (ZnF) domains. We demonstrate that these ZnFs recognize ssRNA with high affinity and specificity. Each ZnF binds to a single AGGUAA motif and the 2 domains combine to recognize AGGUAA (Nx) AGGUAA double sites, suggesting that ZRANB2 regulates alternative splicing via a direct interaction with pre-mRNA at sites that resemble the consensus 5' splice site. We show using X-ray crystallography that recognition of an AGGUAA motif by a single ZnF is dominated by side-chain hydrogen bonds to the bases and formation of a guanine-tryptophan-guanine ''ladder.'' A number of other human proteins that function in RNA processing also contain RanBP2 ZnFs in which the RNA-binding residues of ZRANB2 are conserved. The ZnFs of ZRANB2 therefore define another class of RNA-binding domain, advancing our understanding of RNA recognition and emphasizing the versatility of domains in molecular recognition.

Original languageEnglish
Pages (from-to)5581-5586
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
Publication statusPublished - 7 Apr 2009
Externally publishedYes


  • Protein structure
  • RanBP2 zinc fingers
  • RNA-binding proteins
  • Splicing

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