Biology subjects

Salmon, L. J.

Publications and source records attributed to Salmon, L. J..

3 recordsLinked to original sources

bioRxiv2022

Structural maturation of SYCP1-mediated meiotic chromosome synapsis through conformational remodelling by molecular adapter SYCE3

In meiosis, a supramolecular protein structure, the synaptonemal complex (SC), assembles between homologous chromosomes to facilitate their recombination. 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. 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. We find that SYCP1 tetramers undergo conformational change into 2:1 heterotrimers upon SYCE3-binding, removing their assembly interfaces and disrupting the SYCP1 lattice. SYCE3 then establishes a new lattice by its self-assembly mimicking the role of the disrupted interface in tethering together SYCP1 dimers. SYCE3 also interacts with CE complexes SYCE1-SIX6OS1 and SYCE2-TEX12, providing a mechanism for their recruitment. Thus, SYCE3 remodels the SYCP1 lattice into a CE-binding integrated SYCP1-SYCE3 lattice to achieve long-range synapsis by a mature SC.

biochemistry↗

bioRxiv2020

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

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 m) depends on its midline -fibrous component SYCE2-TEX12. Here, we report X-ray crystal structures of SYCE2-TEX12 as an individual building-block and upon assembly within a fibrous lattice. We combine these structures with mutagenesis, biophysics and electron microscopy to reveal the hierarchical mechanism of SYCE2-TEX12 fibre assembly. SYCE2-TEX12s building-blocks are 2:2 coiled-coils which dimerise into 4:4 hetero-oligomers and interact end-to-end and laterally to form 10-nm fibres, which intertwine within 40-nm bundled micrometre-long fibres that define the SCs midline structure. This assembly mechanism bears striking resemblance with intermediate filament proteins vimentin, lamin and keratin. Thus, SYCE2-TEX12 exhibits behaviour typical of cytoskeletal proteins to provide an -fibrous SC backbone that structurally underpins synaptic elongation along meiotic chromosomes.

biochemistry↗

bioRxiv2019

A pseudo-meiotic centrosomal function of TEX12 in cancer

Cell division by meiosis involves an extraordinary chromosome choreography including pairing, synapsis and crossing over between homologous chromosomes1, 2. The many meiosis-specific genes involved in these processes also constitute a latent toolbox of chromosome remodelling and recombination factors that may be exploited through aberrant expression in cancer3, 4. Here, we report that TEX12, a structural protein involved in meiotic chromosome synapsis5-7, is aberrantly expressed in human cancers, with high TEX12 levels correlating with poor prognosis. We find that TEX12 knock-down causes proliferative failure in multiple cancer cell lines, and confirm its role in the early stages of oncogenesis through murine cancer models. Remarkably, somatically expressed TEX12 localises to centrosomes, leading to altered centrosome number and structure, features associated with cancer development. Further, we identify TEX12 in meiotic centrin-rich bodies, likely precursors of the mitotic centrosome, suggesting that this may represent an additional cellular function of TEX12 in meiosis that has been previously overlooked. Thus, we propose that an otherwise meiotic function of TEX12 in centrosome duplication is responsible for promoting oncogenesis and cellular proliferation in cancer, which may be targeted for novel cancer therapeutics and diagnostics.

cell biology↗