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Structural basis of branching during RNA splicing

Nature Structural & Molecular Biology volume 31, pages 179–189 (2024)Cite this article

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Abstract

Branching is a critical step in RNA splicing that is essential for 5′ splice site selection. Recent spliceosome structures have led to competing models for the recognition of the invariant adenosine at the branch point. However, there are no structures of any splicing complex with the adenosine nucleophile docked in the active site and positioned to attack the 5′ splice site. Thus we lack a mechanistic understanding of adenosine selection and splice site recognition during RNA splicing. Here we present a cryo-electron microscopy structure of a group II intron that reveals that active site dynamics are coupled to the formation of a base triple within the branch-site helix that positions the 2′-OH of the adenosine for nucleophilic attack on the 5′ scissile phosphate. This structure, complemented with biochemistry and comparative analyses to splicing complexes, supports a base triple model of adenosine recognition for branching within group II introns and the evolutionarily related spliceosome.

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Fig. 1: Mechanism of group II intron splicing.
Fig. 2: Conformational dynamics of the branch-site helix during RNA splicing.
Fig. 3: Overall cryo-EM structure of a pre-branching group II intron.
Fig. 4: Active site architecture required for branching.
Fig. 5: DVI helix undergoes remodeling during branching.
Fig. 6: Model for initiation of branch-site dynamics.
Fig. 7: Conservation of branch-site helix architecture.

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Data availability

Structure coordinates and cryo-EM maps have been deposited in the PDB under accession number 8FLI. The cryo-EM maps were also deposited in the Electron Microscopy Data Bank (EMDB) under accession number 29279. Source data are provided with this paper.

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Acknowledgements

We thank S. Fica for helpful comments on the manuscript. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under grant number 5R35GM141706 awarded to N.T. D.L. is supported by NIH U54 AI170855 and the Hearst Foundations developmental chair. D.L. is also supported by the Cancer Center Support Grant to the Salk Institute from the NCI (P30 CA01495). We are also grateful for support to core instrumentation from the Salk Cancer Center (P30CA014195). The molecular graphics and analyses were performed with the USCF Chimera package (supported by NIH P41 GM103311).

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  1. Cheng Zhang

    Present address: Amgen, Thousand Oaks, CA, USA

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA

    Daniel B. Haack, Boris Rudolfs & Navtej Toor

  2. Salk Institute, La Jolla, CA, USA

    Cheng Zhang & Dmitry Lyumkis

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Contributions

D.B.H. and N.T. conceived the project. D.B.H. purified and assembled the complex. D.B.H., B.R. and N.T. designed biochemical experiments. D.B.H. performed the biochemical experiments characterizing the splicing activity of the complex. C.Z. and D.L. collected tilted cryo-EM data. D.B.H., B.R., C.Z. and D.L. processed the cryo-EM data. D.B.H. and B.R. performed model building and structure refinement. D.B.H., B.R. and N.T. analyzed the structure and wrote the manuscript with input from all authors.

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Correspondence to Daniel B. Haack, Dmitry Lyumkis or Navtej Toor.

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Nature Structural & Molecular Biology thanks Guilia Palermo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Sara Osman was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Analysis of cryo-EM density of B* spliceosome.

a. The model corresponding to the 5′ splice site of the B* spliceosome from 6J6Q is shown fit to density at both high and low thresholds. b. The map and original model for the branch helix of the B* spliceosome is shown. The branch-site adenosine is modeled in what appears to be phosphate density. In addition, the surrounding nucleotides do not fit well into the map. c. We remodeled the branch helix from the B* spliceosome to have the branch-site adenosine rotated outwards. This allows a better fit for the surrounding nucleotides into the density for the branch helix.

Extended Data Fig. 2 Secondary structure of T.el4h ΔπΔη′ group II intron.

The T.el4h ΔπΔη′ intron RNA is made up of six highly conserved domains labeled I-VI. Domain I contains several key tertiary interactions that act as a scaffold for the binding of the catalytic components. It also contains the exon binding sequences (EBS1, EBS2, and EBS3) that are responsible for base pairing the intron binding sites (IBS1, IBS2, and IBS3) within the exons to delineate the 5′ and 3′ splice sites. Domain II (blue) participates in two key tertiary interactions (π-π and η-η′) that help to control the branch helix dynamics involved in substrate exchange between steps of splicing. These two interactions are mutated from their native GNRA tetraloops to non-interactive UUCG tetraloops to allow the capture of pre-branching structural intermediates during subsequent cryo-EM experiments. Domain III (yellow) uses its tertiary interactions to help brace the intron and stabilize the active conformation. Domain IV (wheat) contains the open reading frame that encodes the maturase protein and provides the main binding platform for the maturase protein. Domain V (red) is the most highly conserved domain and harbors both the AGC triad and the two-nucleotide bulge that make up the active site of the intron. Domain VI (magenta), also known as the branch helix, contains the adenosine nucleophile (A860) used in the 1st step branching reaction to form the lariat bond with the 5′ SS.

Extended Data Fig. 3 Cryo-EM data processing and validation.

a. Example micrograph. b. Initial 2D class averages. c. Data processing workflow highlighting all relevant steps. d. Fourier Shell Correlation (FSC) curves for cross-validation between the map and model of the pre-branching group II intron. e. Euler angle distribution plot showing the orientations of particles used in the reconstruction. f. Local resolution map of the pre-branching group II intron map (map made in UCSF Chimera). g. Surface sampling plot of the Fourier sampling, with SCF value shown. h. 3D FSC shown as an isosurface at a threshold of 0.5 with three perpendicular planar views.

Extended Data Fig. 4 Cryo-EM density of a group II intron in the presence of Ca2+.

Cryo-EM density is shown from a data set collected on the WT T.el4h group II intron RNP in the presence of 5 mM Ca2+. Domain VI (magenta) is clearly visible in the vertical position. With DVI in this position, the branch-site adenosine is located ∼20 Å from the 5′ splice site, therefore no structural insights could be gained into the mechanism of branching.

Extended Data Fig. 5 Occurrence of the cis A:rC base pair.

a. The cis A:rC base pair found within the branch helix of the T.el4h group II intron is shown. This interaction is responsible for recognizing and positioning the branch-site adenosine for catalysis. b. This A:rC pair is conserved within the branch-site helix of the post-branching yeast spliceosome (PDB 5LJ3)4. c. This A:rC pair is found within the large subunit of the ribosome (PDB 3J79)55. d. A high resolution X-ray crystal structure of the mosquito-borne flavivirus dumbbell RNA also contains this A:rC pair (PDB 7KGA)23. Rigid body fitting of the group II intron A:rC pair into the high-quality electron density from the flavivirus dumbbell RNA shows a good fit.

Extended Data Fig. 6 T.el4h mutant constructs used during in vitro splicing assay.

The secondary structure of DVI is shown for WT and the mutants tested in the in vitro splicing assay. The G832-C858 pair is shown in light blue and the branch-site adenosine (A860) is shown in yellow. Mutations are highlighted in black. The constructs are grouped and colored as seen in Fig. 3B of the main text.

Extended Data Fig. 7 In vitro splicing gel.

Products of in vitro spliced group II introns were analyzed using polyacrylamide gel electrophoresis (PAGE). Bands corresponding to precursor, lariat, and ligated exons are clearly visible and can be unambiguously assigned. Each construct was tested in triplicate except for G832A/C858U which required a fourth trial due to a loading error for trial 3. Fraction branched was calculated as described in the methods section.

Extended Data Fig. 8 Structural basis for the conservation of the branch-site adenosine.

a. For the WT T.el4h intron, the branch-site adenosine A860 (yellow) forms a cis Watson-Crick:sugar edge pair with C858. The geometry of the hydrogen bonds making up this interaction are shown by yellow dashes and the distances are displayed in Å (black). b. If A860 is mutated to a guanosine (A860G) a hydrogen bonding clash (red arks) would form between the O2 of C858 and the O6 G860. c. In the case where A860 is mutated to a cytosine (A860C), the smaller pyrimidine nucleobase does not allow the N3 or N4 of the cytosine to effectively interact with C858 (red X). d. Lastly, if A860 was mutated to a uridine (A860U) a combination of noncomplementary hydrogen bonding and long interacting distances would lead to mispositioning of the branching nucleophile.

Extended Data Fig. 9 DV in the pre-branching state is in an active conformation.

The AGC triad and two-nt bulge of DV (red) are shown with the M1 and M2 catalytic metal ions bound (orange). Coordination of the metals is shown as yellow dashed lines. M1 and M2 are 6.4 Å apart (dashed black line) requiring DV to undergo a small conformational change to bring the metals into the proximity required for catalysis. The metal ion distance provides a rational for why the pre-branching state was captured. A black arrow indicates the nucleophilic attack performed during branching once the metal ion binding pocket tightens. In addition, both the bulged adenosine (yellow) and the scissile phosphate of U1 (green) are both in position to perform the branching reaction. The sharpened map corresponding to the pre-branching state is shown overlayed with the model to highlight the fit.

Extended Data Fig. 10 Sequence alignment of DVI of the group IIB intron and the U2 snRNA of the spliceosome.

The sequence proximal to the branch-site of 129 group IIB introns were aligned using BioEdit alignment software as described in the methods. The numbering of the nucleotides follows that of the T.el4h intron. Analysis of the aligned sequences showed complete conservations of the branch-site nucleophile as an adenosine (A860). In addition, there was also complete conservation for 832 as a purine and 858 as a pyrimidine. Furthermore, the base pair formed between nucleotides 832 and 858 never deviate from Watson-Crick. The sequence alignment was used to create the consensus secondary structure and covariation matrix for the 832–858 base pair shown in Fig. 6A of the main text. This sequence conservation correlates well with the in vitro splicing assay data where only the G832A/C858U mutant maintained wild type branching activity. For the U2 snRNA alignment, sequences from 24 diverse species were selected and the portions homologous to the AGC triad and DVI of the group II intron were aligned using BioEdit alignment software. In both cases the RNA is highly conserved with only small deviations to the U2 snRNA where it pairs to the intron to form the branch helix. The alignment also shows that the homologous nucleotide to 832 of group II introns is completely conserved as an adenosine (A35) in the spliceosome. The alignment data for the U2 snRNA was used to create the consensus secondary structure and covariation matrix seen in Fig. 6A of the main text.

Supplementary information

Reporting Summary

Supplementary Video 1

A Pymol morph video of the transition between the pre- and post-branching states of a group II intron. Dynamics observed in the catalytic DV may propagate to the branch helix DVI resulting in rearrangements of the bulged adenosine after branching.

Source data

Source Data Fig. 1

Raw file of the ethidium bromide-stained gel.

Source Data Fig. 4

Raw files from typhoon scans. Gels have been annotated for clarity.

Source Data Fig. 5

Raw file from typhoon scan.

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Haack, D.B., Rudolfs, B., Zhang, C. et al. Structural basis of branching during RNA splicing. Nat Struct Mol Biol 31, 179–189 (2024). https://doi.org/10.1038/s41594-023-01150-0

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