RNA sculpting by the primordial Helix-clasp-Helix–Strand-Loop (HcH–SL) motif enforces chemical recognition enabling diverse KH domain functions

Tainer, John A.; Tsutakawa, Susan E.

doi:10.1016/j.jbc.2025.108474

RNA sculpting by the primordial Helix-clasp-Helix–Strand-Loop (HcH–SL) motif enforces chemical recognition enabling diverse KH domain functions

Journal Article · Wed Apr 02 00:00:00 EDT 2025 · Journal of Biological Chemistry

DOI:https://doi.org/10.1016/j.jbc.2025.108474· OSTI ID:2547060

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Univ. of Texas, Houston, TX (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

In all domains of life, the ancient K homology (KH) domain superfamily is central to RNA processes including splicing, transcription, posttranscriptional gene regulation, signaling, and translation. Proteins with 1 to 15 KH domains bind single-strand (ss) RNA or DNA with base sequence specificity. Here, we examine over 40 KH domain experimental structures in complex with nucleic acid (NA) and define a novel Helix-clasp-Helix–Strand-Loop (HcH–SL) NA recognition motif binding 4 to 5 nucleotides using 10 to 18 residues. HcH–SL includes and extends the Gly-X-X-Gly (GXXG) signature sequence “clasp” that brings together two helices as an ∼90° helical corner. The first helix primarily provides side chain interactions to unstack and sculpt 2 to 3 bases on the 5′ end for recognition of sequence and chemistry. The clasp and second helix amino dipole recognize a central phosphodiester. Following the helical corner, a beta strand and its loop extension recognize the two 3′ nucleotides, primarily through main chain interactions. The HcH–SL structural motif forms a right-handed triangle and concave functional interface for NA interaction that unexpectedly splays four bound nucleotides into conformations matching RNA recognition motif (RRM) bound RNA structures. Evolutionary analyses and its ability to recognize base sequence and chemistry make HcH–SL a primordial NA binding motif distinguished by its binding mode from other NA structural recognition motifs: helix-turn-helix, helix-hairpin-helix, and beta strand RRM motifs. Combined results explain its vulnerability as a viral hijacking target and how mutations and expression defects lead to diverse diseases spanning cancer, cardiovascular, fragile X syndrome, neurodevelopmental disorders, and paraneoplastic disease.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE; USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2547060

Alternate ID(s):: OSTI ID: 2571377

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 5 Vol. 301; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
DNA binding domain
KH domain
RNA base binding motif
cancer
helical dipole
main chain
protein structure
side chain
splicing
transcription
translation

RNA sculpting by the primordial Helix-clasp-Helix–Strand-Loop (HcH–SL) motif enforces chemical recognition enabling diverse KH domain functions

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