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Instruments / Technical Area	Publication Details	Published
B21-High Throughput SAXS	A molecular model for self-assembly of the synaptonemal complex protein SYCE3 Orla M. Dunne , Owen R. Davies Journal Of Biological Chemistry DOI: 10.1074/jbc.RA119.008404 Diamond Proposal Number(s): [14435, 15580, 15836, 15897] Open Access Show Abstract ▼ Abstract: The synaptonemal complex (SC) is a supramolecular protein assembly that mediates homologous chromosome synapsis during meiosis. This zipper-like structure assembles in a continuous manner between homologous chromosome axes, enforcing a 100-nm separation along their entire length, and providing the necessary three-dimensional framework for crossover formation. The mammalian SC comprises eight components—synaptonemal complex protein 1–3 (SYCP1–3), synaptonemal complex central element protein 1–3 (SYCE1–3), testis expressed 12 (TEX12), and six6 opposite strand transcript 1 (SIX6OS1)—arranged in transverse and longitudinal structures. These largely α-helical, coiled-coil proteins undergo heterotypic interactions, coupled with recursive self-assembly of SYCP1, SYCE2–TEX12, and SYCP2–SYCP3, to achieve the vast supramolecular SC structure. Here, we report a novel self-assembly mechanism of the SC central element component SYCE3, identified through multi-angle light scattering and small-angle X-ray scattering (SAXS) experiments. These analyses revealed that SYCE3 adopts a dimeric four-helical bundle structure that acts as the building block for concentration-dependent self-assembly into a series of discrete higher-order oligomers. We observed that this is achieved through staggered lateral interactions between self-assembly surfaces of SYCE3 dimers and through end-on interactions that likely occur through intermolecular domain swapping between dimer folds. These mechanisms are combined to achieve potentially limitless SYCE3 assembly, particularly favoring formation of dodecamers of three laterally associated end-on tetramers. Our findings extend the family of self-assembling proteins within the SC and reveal additional means for structural stabilization of the SC central element.	Apr 2019
B21-High Throughput SAXS	Molecular structure of human synaptonemal complex protein SYCE1 Orla M. Dunne , Owen R. Davies Chromosoma 14 DOI: 10.1007/s00412-018-00688-z Diamond Proposal Number(s): [15580, 15836, 15897] Open Access Show Abstract ▼ Abstract: The reduction in chromosome number during meiosis is essential for the production of haploid germ cells and thereby fertility. To achieve this, homologous chromosomes are first synapsed together by a protein assembly, the synaptonemal complex (SC), which permits genetic exchange by crossing over and the subsequent accurate segregation of homologues. The mammalian SC is formed of a zipper-like array of SYCP1 molecules that bind together homologous chromosomes through self-assembly in the midline that is structurally supported by the central element. The SC central element contains five proteins—SYCE1, SYCE3, SIX6OS1, and SYCE2-TEX12—that permit SYCP1 assembly to extend along the chromosome length to achieve full synapsis. Here, we report the structure of human SYCE1 through solution biophysical methods including multi-angle light scattering and small-angle X-ray scattering. The structural core of SYCE1 is formed by amino acids 25–179, within the N-terminal half of the protein, which mediates SYCE1 dimerization. This α-helical core adopts a curved coiled-coil structure of 20-nm length in which the two chains are arranged in an anti-parallel configuration. This structure is retained within full-length SYCE1, in which long C-termini adopt extended conformations to achieve an elongated molecule of over 50 nm in length. The SYCE1 structure is compatible with it functioning as a physical strut that tethers other components to achieve structural stability of the SC central element.	Jan 2019
B21-High Throughput SAXS I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1 James M. Dunce , Amy E. Milburn , Manickam Gurusaran , Irene Da Cruz , Lee T. Sen , Ricardo Benavente , Owen R. Davies Nature Communications 9 DOI: 10.1038/s41467-018-07794-7 Diamond Proposal Number(s): [13587, 15836, 18598] Open Access Show Abstract ▼ Abstract: Meiotic chromosomes undergo rapid prophase movements, which are thought to facilitate the formation of inter-homologue recombination intermediates that underlie synapsis, crossing over and segregation. The meiotic telomere complex (MAJIN, TERB1, TERB2) tethers telomere ends to the nuclear envelope and transmits cytoskeletal forces via the LINC complex to drive these rapid movements. Here, we report the molecular architecture of the meiotic telomere complex through the crystal structure of MAJIN-TERB2, together with light and X-ray scattering studies of wider complexes. The MAJIN-TERB2 2:2 hetero-tetramer binds strongly to DNA and is tethered through long flexible linkers to the inner nuclear membrane and two TRF1-binding 1:1 TERB2-TERB1 complexes. Our complementary structured illumination microscopy studies and biochemical findings reveal a telomere attachment mechanism in which MAJIN-TERB2-TERB1 recruits telomere-bound TRF1, which is then displaced during pachytene, allowing MAJIN-TERB2-TERB1 to bind telomeric DNA and form a mature attachment plate.	Dec 2018
B21-High Throughput SAXS I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Structural basis of meiotic chromosome synapsis through SYCP1 self-assembly James M. Dunce , Orla M. Dunne , Matthew Ratcliff , Claudia Millán , Suzanne Madgwick , Isabel Uson , Owen R. Davies Nature Structural & Molecular Biology 7 DOI: 10.1038/s41594-018-0078-9 Diamond Proposal Number(s): [9948, 13587, 14435, 15580, 15897] Open Access Show Abstract ▼ Abstract: Meiotic chromosomes adopt unique structures in which linear arrays of chromatin loops are bound together in homologous chromosome pairs by a supramolecular protein assembly, the synaptonemal complex. This three-dimensional scaffold provides the essential structural framework for genetic exchange by crossing over and subsequent homolog segregation. The core architecture of the synaptonemal complex is provided by SYCP1. Here we report the structure and self-assembly mechanism of human SYCP1 through X-ray crystallographic and biophysical studies. SYCP1 has an obligate tetrameric structure in which an N-terminal four-helical bundle bifurcates into two elongated C-terminal dimeric coiled-coils. This building block assembles into a zipper-like lattice through two self-assembly sites. N-terminal sites undergo cooperative head-to-head assembly in the midline, while C-terminal sites interact back to back on the chromosome axis. Our work reveals the underlying molecular structure of the synaptonemal complex in which SYCP1 self-assembly generates a supramolecular lattice that mediates meiotic chromosome synapsis.	Jun 2018
I03-Macromolecular Crystallography	A molecular model for the role of SYCP3 in meiotic chromosome organisation Johanna Syrjanen , Luca Pellegrini , Owen Davies Elife 3 DOI: 10.7554/eLife.02963 PMID: 24950965 Open Access Show Abstract ▼ Abstract: The synaptonemal complex (SC) is an evolutionarily-conserved protein assembly that holds together homologous chromosomes during prophase of the first meiotic division. Whilst essential for meiosis and fertility, the molecular structure of the SC has proved resistant to elucidation. The SC protein SYCP3 has a crucial but poorly understood role in establishing the architecture of the meiotic chromosome. Here we show that human SYCP3 forms a highly-elongated helical tetramer of 20 nm length. N-terminal sequences extending from each end of the rod-like structure bind double-stranded DNA, enabling SYCP3 to link distant sites along the sister chromatid. We further find that SYCP3 self-assembles into regular filamentous structures that resemble the known morphology of the SC lateral element. Together, our data form the basis for a model in which SYCP3 binding and assembly on meiotic chromosomes leads to their organisation into compact structures compatible with recombination and crossover formation.	Jun 2014
I03-Macromolecular Crystallography	Defining the Molecular Basis of BubR1 Kinetochore Interactions and APC/C-CDC20 Inhibition Sheena D'arcy , Owen R. Davies , Tom L. Blundell , Victor M. Bolanos-garcia Journal Of Biological Chemistry 285 (19), 14764 - 14776 DOI: 10.1074/jbc.M109.082016 PMID: 20220147 Show Abstract ▼ Abstract: BubR1 is essential for the mitotic checkpoint that prevents aneuploidy in cellular progeny by triggering anaphase delay in response to kinetochores incorrectly/not attached to the mitotic spindle. Here, we define the molecular architecture of the functionally significant N-terminal region of human BubR1 and present the 1.8 Å crystal structure of its tetratricopeptide repeat (TPR) domain. The structure reveals divergence from the classical TPR fold and is highly similar to the TPR domain of budding yeast Bub1. Shared distinctive features include a disordered loop insertion, a 310-helix, a tight turn involving glycine positive Φ angles, and noncanonical packing of and between the TPR motifs. We also define the molecular determinants of the interaction between BubR1 and kinetochore protein Blinkin. We identify a shallow groove on the concave surface of the BubR1 TPR domain that forms multiple discrete and potentially cooperative interactions with Blinkin. Finally, we present evidence for a direct interaction between BubR1 and Bub1 mediated by regions C-terminal to their TPR domains. This interaction provides a mechanism for Bub1-dependent kinetochore recruitment of BubR1. We thus present novel molecular insights into the structure of BubR1 and its interactions at the kinetochore-microtubule interface. Our studies pave the way for future structure-directed engineering aimed at dissecting the roles of kinetochore-bound and other pools of BubR1 in vivo.	Apr 2010

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