( a) Mammalian SC structure is defined by a supramolecular SYCP1 tetramer lattice, in which tetramer interfaces bind together parallel SYCP1 dimers and support cooperative head-to-head interactions between αNtip sites of bioriented SYCP1 tetramers, which are anchored to chromosome axes through back-to-back assembly of their α-helical C-termini ( Dunce et al., 2018). SYCP1 interacts with central element protein SYCE3. This hierarchical zipper-like model for SC assembly is supported by analysis of mice carrying mutations in these SC proteins, which exhibit defects at the expected stages of SC assembly with failure to recruit downstream SC proteins, and resultant chromosome asynapsis, spermatocyte death and infertility in males ( Bolcun-Filas et al., 2007 Bolcun-Filas et al., 2009 de Vries et al., 2005 Gomez et al., 2016 Hamer et al., 2006 Hamer et al., 2008 Schramm et al., 2011).
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Head-to-head interactions between SYCP1’s N-termini are reinforced by recruitment of CE proteins SYCE3, SYCE1-SIX6OS1, and finally SYCE2-TEX12, which confer stability to the SC and allow its extension along the chromosome axis to achieve full synapsis. SYCP1 transverse filaments then assemble between aligned axes, organised with the C-termini of this coiled-coil protein within the lateral elements, and its N-termini within a midline central element (CE) ( Figure 1a) ( de Vries et al., 2005 Schucker et al., 2015). Firstly, SYCP3-containing axial/lateral elements assemble along individual unaligned chromosome axes, which subsequently become aligned in homologous pairs by recombination. Mammalian SC assembly is thought to occur via a hierarchical zipper-like mechanism ( Cahoon and Hawley, 2016 Fraune et al., 2012). The SC is a ribbon-like structure of up to 24 μm length in humans ( Solari, 1980), which assembles between aligned chromosome axes at typically 400 nm initial separation, and brings their parallel axes into 100 nm synapsis ( Hunter, 2015 Zickler and Kleckner, 2015). However, the mechanism of mammalian SC assembly remains poorly understood. The structural integrity of the SC is essential for meiosis across eukaryotes ( Zickler and Kleckner, 2015), and SC defects are associated with human infertility, miscarriage and aneuploidy ( Fan et al., 2021 Geisinger and Benavente, 2016 Schilit et al., 2020). The mature SC structure then provides the necessary three-dimensional framework for DSB repair and crossover formation ( Hunter, 2015 Zickler and Kleckner, 2015). SC assembly is directed by the inter-homologue alignments established at recombination intermediates formed at sites of induced double-strand breaks (DSBs) ( Romanienko and Camerini-Otero, 2000). This requires a supramolecular protein structure, the synaptonemal complex (SC), which binds homologous chromosomes together, in synapsis, to facilitate recombination ( Hunter, 2015 Zickler and Kleckner, 2015). In meiosis, haploid germ cells are formed through the segregation of homologous chromosomes following their genetic exchange by crossing over. Thus, SYCE3 remodels the SYCP1 lattice into a CE-binding integrated SYCP1-SYCE3 lattice to achieve long-range synapsis by a mature SC. SYCE3 also interacts with CE complexes SYCE1-SIX6OS1 and SYCE2-TEX12, providing a mechanism for their recruitment. SYCE3 then establishes a new lattice by its self-assembly mimicking the role of the disrupted interface in tethering together SYCP1 dimers. We find that SYCP1 tetramers undergo conformational change into 2:1 heterotrimers upon SYCE3-binding, removing their assembly interfaces and disrupting the SYCP1 lattice. Here, we combine biochemical approaches with separation-of-function mutagenesis in mice to uncover that, rather than stabilising the SYCP1 lattice, the CE protein SYCE3 actively remodels this structure during synapsis. Mammalian SC formation is thought to involve hierarchical zipper-like assembly of an SYCP1 protein lattice that recruits stabilising central element (CE) proteins as it extends. In meiosis, a supramolecular protein structure, the synaptonemal complex (SC), assembles between homologous chromosomes to facilitate their recombination.
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