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Structural basis of meiotic chromosome synaptic elongation through hierarchical fibrous assembly of SYCE2-TEX12

Nature Structural & Molecular Biology volume 28, pages 681–693 (2021)Cite this article

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Abstract

The synaptonemal complex (SC) is a supramolecular protein assembly that mediates synapsis between homologous chromosomes during meiosis. SC elongation along the chromosome length (up to 24 μm) depends on its midline α-fibrous component SYCE2-TEX12. Here, we report X-ray crystal structures of human SYCE2-TEX12 as an individual building block and on assembly within a fibrous lattice. We combine these structures with mutagenesis, biophysics and electron microscopy to reveal the hierarchical mechanism of SYCE2-TEX12 fiber assembly. SYCE2-TEX12’s building blocks are 2:2 coiled coils that dimerize into 4:4 hetero-oligomers and interact end-to-end and laterally to form 10-nm fibers that intertwine within 40-nm bundled micrometer-long fibers that define the SC’s midline structure. This assembly mechanism bears striking resemblance with intermediate filament proteins vimentin, lamin and keratin. Thus, SYCE2-TEX12 exhibits behavior typical of cytoskeletal proteins to provide an α-fibrous SC backbone that structurally underpins synaptic elongation along meiotic chromosomes.

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Fig. 1: SYCE2-TEX12 self-assembly is driven by the C-terminal tip of TEX12.
Fig. 2: Crystal structure of the SYCE2-TEX12 core 2:2 complex.
Fig. 3: Crystal structure of the SYCE2-TEX12 core 4:4 complex.
Fig. 4: A molecular model of the SYCE2-TEX12 core ‘closed’ 4:4 assembly.
Fig. 5: Molecular determinants of SYCE2-TEX12 self-assembly by TEX12’s C-terminal tip.
Fig. 6: A molecular model of the SYCE2-TEX12 core fibrous assembly.
Fig. 7: A molecular mechanism for fibrous assembly of SYCE2-TEX12.

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Data availability

Crystallographic structure factors and atomic coordinates have been deposited in the Protein Data Bank (PDB) under accession numbers 6R17 and 6YQF, and their corresponding raw diffraction images have been deposited at https://proteindiffraction.org/. Source data are provided with this paper.

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Acknowledgements

We thank Diamond Light Source and the staff of beamlines I03, I24 and B21 (proposals mx13587, mx18598, sm14435, sm15580, sm15897, sm15836 and sm21777). We thank I. Usón for advice on ARCIMBOLDO_LITE, and A. Baslé and H. Waller for assistance with X-ray crystallographic and circular dichroism data collection. This study was supported by a Wellcome Trust Senior Research Fellowship (grant no. 219413/Z/19/Z) (O.R.D.).

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Author notes

  1. James M. Dunce

    Present address: Department of Biochemistry, University of Cambridge, Old Addenbrookes Site, Cambridge, UK

Authors and Affiliations

  1. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, UK

    James M. Dunce, Lucy J. Salmon & Owen R. Davies

  2. Wellcome Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh, UK

    Owen R. Davies

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Contributions

J.M.D. crystallized SYCE2-TEX12 2:2 and 4:4 complexes and performed biophysical and EM experiments. L.J.S. collected initial biophysics data. O.R.D. solved the SYCE2-TEX12 crystal structures, analyzed data, designed experiments and wrote the paper.

Corresponding author

Correspondence to Owen R. Davies.

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The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors declare no competing interests.

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Peer review information Nature Structural & Molecular Biology thanks John Weir and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Beth Moorefield 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 Circular dichroism analysis of SYCE2-TEX12 complexes.

(a-c) Circular dichroism (CD) analysis of SYCE2-TEX12 core and full-length complexes containing wild-type (WT; purple) and ΔCtip (yellow) TEX12 sequences. (a) Far UV circular dichroism (CD) spectra recorded between 260 nm and 185 nm in mean residue ellipticity, MRE ([θ]) (x103 deg.cm2.dmol−1.residue−1). Data were deconvoluted using the CDSSTR algorithm, with helical content indicated. (b-c) CD thermal denaturation of SYCE2-TEX12 (b) core and (c) full-length complexes, recording the CD helical signature at 222 nm between 5 °C and 95 °C, as % unfolded. Melting temperatures were estimated, as indicated.

Extended Data Fig. 2 Image analysis of SYCE2-TEX12 electron micrographs.

(a-d) The procedure used for automated image analysis and quantification of SYCE2-TEX12 fibers is shown for an example micrograph. The Fiji distribution of ImageJ was used to process (a) raw micrographs through (b) background subtraction and (c) FFT Bandpass filter. (d) Fibers were detected by the Ridge detection algorithm in which the centre and edges of interpreted fibres were highlighted in red and green, respectively, from which mean fiber widths and fibre lengths were determined. Representative of at least three independent experiments.

Extended Data Fig. 3 Electron microscopy analysis of SYCE2-TEX12.

(a-d) Electron microscopy of SYCE2-TEX12 (a,b) core and (c,d) wild-type, relating to Fig. 1f,g. (a) Scatter plot of mean fibre width (d, nm) against fibre length (nm) for wild-type SYCE2-TEX12 core. (b) Histograms of the number of fibres with mean widths within 2-nm bins for SYCE2-TEX12 core wild-type (dark blue), ΔCtip (yellow), FFV (F102A, F109A, V116A; purple) and LFIL (L110E, F114E, I117E, L121E; green). The mean, standard deviation and number of fibres in each population is shown, each determined from nine micrographs. (c) Scatter plot of mean fibre width (d, nm) against fibre length (nm) for wild-type SYCE2-TEX12. (d) Histograms of the number of fibres with mean widths within 2-nm bins for SYCE2-TEX12 full-length wild-type (dark blue), ΔCtip (yellow), FFV (light blue) and LFIL (green). The mean, standard deviation and number of fibres in each population is shown, each determined from nine micrographs.

Source data

Extended Data Fig. 4 Crystal structure of the SYCE2-TEX12 core 2:2 complex.

(a) 2Fo-Fc electron density map of the SYCE2-TEX12 core ΔCtip 2:2 complex, presented as a rainbow between 1.0σ (blue) and 3.5σ (red), superimposed on the refined crystallographic model. (b-c) SEC-SAXS analysis of SYCE2-TEX12 core ΔS2C/ΔCtip. (b) SAXS Guinier analysis to determine the radius of gyration (Rg); linear fits are shown in red, with the fitted data range highlighted in black and demarcated by dashed lines. The Q.Rg values were < 1.3 and Rg was calculated as 41 Å and 49 Å, respectively. (c) SAXS Guinier analysis to determine the radius of gyration of the cross-section (Rc); linear fits are shown in red, with the fitted data range highlighted in black and demarcated by dashed lines. The Q.Rc values were < 1.3 and Rc was calculated as 11.7 Å and 12.2 Å, respectively. (d) SEC–MALS analysis of SYCE2-TEX12 core ΔS2C/ΔCtip (dRI profile with molecular weights plotted as diamonds) showing the formation of a 39 kDa 2:2 complex (86%; theoretical – 40 kDa) and a 79 kDa 4:4 complex (14%; theoretical – 79 kDa). (e) Theoretical model of the full SYCE2-TEX12 core ΔCtip 2:2 complex in which the missing C-terminal coiled-coil and S2C helix were docked onto the crystal structure.

Extended Data Fig. 5 Crystal structure of the SYCE2-TEX12 core 4:4 complex.

(a) 2Fo-Fc electron density map of the SYCE2-TEX12 core ΔCtip 4:4 complex (1.0σ), presented as a rainbow between 1.0σ (blue) and 3.5σ (red), superimposed on the refined crystallographic model. (b) Superposition of a constituent 2:2 complex from the SYCE2-TEX12 core ΔCtip 4:4 structure (light blue and light red) and the SYCE2-TEX12 core ΔCtip 2:2 structure (dark blue and dark red), with r.m.s. deviation of 1.91. (c) SEC-MALS analysis of SYCE2-TEX12 core MBP-fusion proteins (dRI profiles with molecular weights plotted as diamonds). SYCE2-TEX12 core wild-type is a 296 kDa 4:4 complex (theoretical – 278 kDa), whereas ΔS2C and ΔCtip form 131 kDa and 130 kDa 2:2 complexes, respectively (theoretical – 136 kDa and 137 kDa).

Extended Data Fig. 6 MALS and SAXS analysis of SYCE2-TEX12 wild-type and mutant complexes.

(a) SEC-MALS analysis of SYCE2-TEX12 core ΔS2C and V149E, V153E, V156E and L160E mutants (dRI profiles with molecular weights plotted as diamonds), demonstrating the formation of 47 kDa and 45 kDa 2:2 complexes, respectively (theoretical – 42 kDa and 45 kDa). The wild-type 90 kDa 4:4 complex is shown in grey for comparison. (b-g) SEC-SAXS analysis of SYCE2-TEX12 core wild-type, F102A F109A V116A (FFV) and L110E F114E I117E L121E (LFIL) mutants. (b) SAXS scattering data overlaid with the theoretical scattering curves of the 4:4 crystal structure (red), with modeled Ctip-S2C C-terminal bundles (blue), and with flexibly modelled N-termini (yellow); χ2 values are indicated and residuals for each fit are shown (inset). (c) SAXS Guinier analysis to determine the radius of gyration (Rg); linear fits are shown in red, with the fitted data range highlighted in black and demarcated by dashed lines. The Q.Rg values were < 1.3 and Rg was calculated as 49 Å, 49 Å and 47 Å, respectively. (d-e) SAXS Guinier analysis to determine the radius of gyration of the cross-section (Rc); linear fits are shown in red, with the fitted data range highlighted in black and demarcated by dashed lines. The Q.Rc values were < 1.3 and Rc was calculated as (d) 19.4 Å for wild-type and FFV and (e) 12.2 Å for LFIL. (f) SAXS P(r) interatomic distance distributions of SYCE2-TEX12 core FFV and LFIL, showing maximum dimensions of 19 nm and 18 nm, respectively. (g) SAXS ab initio model of SYCE2-TEX12 core FFV in which a filtered averaged model from 30 independent DAMMIF runs is shown.

Extended Data Fig. 7 Modelling of the SYCE2-TEX12 core ‘closed’ 4:4 assembly.

(a-c) Modelling of the ‘closed’ 4:4 assembly. (a) Theoretical model of hetero-dimeric coiled-coils corresponding to SYCE2 and TEX12 amino-acids 114-165 and 75-123, respectively (including Ctip and S2C sequences 155-165 and 114-123), were generated using CCBuilder by specifying the heptad register observed in the 2:2 and 4:4 crystal structures. (b) The coiled-coil model (red and blue) docked onto the 2:2 ends of the 4:4 crystal structure (pale red and pale blue), showing close correspondence between overlapping helices. (c) This resulted in a 4:4 structure with emanating S2C-Ctip dimers (top) that was subjected to iterative energy minimisation and geometry idealisation such that S2C-Ctip sequences of adjacent dimers combined into capping four-helical bundles at either end of the 4:4 molecule (bottom).

Extended Data Fig. 8 Modelling of the SYCE2-TEX12 core fibrous assembly.

(a) Model of SYCE2-TEX12 core fibrous assembly in which adjacent 4:4 complexes are translated by 15 nm and interact back-to-back through stacked S2C-Ctip antiparallel four-helical bundles. (b-e) SEC-SAXS analysis of SYCE2-TEX12 core 35 nm and 65 nm (length) fibres. (b) SAXS scattering data overlaid with the theoretical scattering curves of a 4 × 35 nm (w × l) fibre model (two consecutive 4:4 complexes, red) and a 2 × 65 nm (w × l) fibre model (four consecutive 2:2 complexes, blue); χ2 values are indicated and residuals for each fit are shown (inset). (c) The 4 × 35 nm and 2 × 65 nm fibre models used for SAXS data fitting. (d) SAXS Guinier analysis to determine the radius of gyration (Rg); linear fits are shown in red, with the fitted data range highlighted in black and demarcated by dashed lines. The Q.Rg values were < 1.3 and Rg was calculated as 86 Å and 167 Å, respectively. (e) SAXS Guinier analysis to determine the radius of gyration of the cross-section (Rc); linear fits are shown in red, with the fitted data range highlighted in black and demarcated by dashed lines. The Q.Rc values were < 1.3 and Rc was calculated as 16.6 Å and 15.3 Å, respectively.

Extended Data Fig. 9 Comparison of hierarchical assembly by SYCE2-TEX12 and intermediate filaments.

(a,b) Side-by-side comparison of assembly by (a) SYCE2-TEX12 and (b) intermediate filaments, using examples of keratin and vimentin. (a) SYCE2-TEX12 undergoes hierarchical assembly from a 2:2 into 4:4 complex, and through end-on assembly into 2-nm and 4-nm fibres, which assemble into 10-nm fibres that become bundled together in 40-nm fibres that represent its dominant state by electron microscopy. Scale bars, 20 nm (top), 50 nm (middle), 100 nm (bottom, upper) and 50 nm (bottom, lower). (b) The keratin K1/K10-1B complex is a dimer that forms an anti-parallel hetero-tetramer (PDB accession 6EC0)53. Higher order assembly occurs through unit length filaments, into 10-nm fibres, which are directly comparable to SYCE2-TEX12 10-nm fibres, and are shown here for vimentin (middle). Scale bars, 100 nm. Reproduced from Helfand, et al.54. The 10-nm IF fibres can further assemble into thick bundles, which are directly comparable with SYCE2-TEX12 40-nm fibres. Please see Kayser, et al.58 for electron micrographs of keratin’s thick bundles.

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Dunce, J.M., Salmon, L.J. & Davies, O.R. Structural basis of meiotic chromosome synaptic elongation through hierarchical fibrous assembly of SYCE2-TEX12. Nat Struct Mol Biol 28, 681–693 (2021). https://doi.org/10.1038/s41594-021-00636-z

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