Structural analysis of the human SYCE2–TEX12 complex provides molecular insights into synaptonemal complex assembly

The successful completion of meiosis is essential for all sexually reproducing organisms. The synaptonemal complex (SC) is a large proteinaceous structure that holds together homologous chromosomes during meiosis, providing the structural framework for meiotic recombination and crossover formation. Errors in SC formation are associated with infertility, recurrent miscarriage and aneuploidy. The current lack of molecular information about the dynamic process of SC assembly severely restricts our understanding of its function in meiosis. Here, we provide the first biochemical and structural analysis of an SC protein component and propose a structural basis for its function in SC assembly. We show that human SC proteins SYCE2 and TEX12 form a highly stable, constitutive complex, and define the regions responsible for their homotypic and heterotypic interactions. Biophysical analysis reveals that the SYCE2–TEX12 complex is an equimolar hetero-octamer, formed from the association of an SYCE2 tetramer and two TEX12 dimers. Electron microscopy shows that biochemically reconstituted SYCE2–TEX12 complexes assemble spontaneously into filamentous structures that resemble the known physical features of the SC central element (CE). Our findings can be combined with existing biological data in a model of chromosome synapsis driven by growth of SYCE2–TEX12 higher-order structures within the CE of the SC.

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SUMO Localizes to the Central Element of the Synaptonemal Complex and is Essential for Meiotic Chromosome Synapsis in Saccharomyces cerevisiae

10.14418/wes01.2.45 ◽

2013 ◽

Author(s):

Louis Fong Taylor

Keyword(s):

Saccharomyces Cerevisiae ◽

Synaptonemal Complex ◽

Meiotic Chromosome ◽

Central Element ◽

Chromosome Synapsis

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Faculty Opinions recommendation of Structural basis for inverting the enantioselectivity of arylmalonate decarboxylase revealed by the structural analysis of the Gly74Cys/Cys188Ser mutant in the liganded form.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2606963.2265061 ◽

2010 ◽

Author(s):

Reinhard Sterner ◽

Patrick Babinger

Keyword(s):

Structural Analysis ◽

Structural Basis ◽

Arylmalonate Decarboxylase

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Identification of fidelity-governing factors in human recombinases DMC1 and RAD51 from cryo-EM structures

Nature Communications ◽

10.1038/s41467-020-20258-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shih-Chi Luo ◽

Hsin-Yi Yeh ◽

Wei-Hsuan Lan ◽

Yi-Min Wu ◽

Cheng-Han Yang ◽

...

Keyword(s):

Functional Analysis ◽

Structural Analysis ◽

Md Simulation ◽

Structural Basis ◽

High Fidelity ◽

Dna Dynamics ◽

Genomic Integrity ◽

Mismatched Dna ◽

Dna Backbone ◽

Loop 2

AbstractBoth high-fidelity and mismatch-tolerant recombination, catalyzed by RAD51 and DMC1 recombinases, respectively, are indispensable for genomic integrity. Here, we use cryo-EM, MD simulation and functional analysis to elucidate the structural basis for the mismatch tolerance of DMC1. Structural analysis of DMC1 presynaptic and postsynaptic complexes suggested that the lineage-specific Loop 1 Gln244 (Met243 in RAD51) may help stabilize DNA backbone, whereas Loop 2 Pro274 and Gly275 (Val273/Asp274 in RAD51) may provide an open “triplet gate” for mismatch tolerance. In support, DMC1-Q244M displayed marked increase in DNA dynamics, leading to unobservable DNA map. MD simulation showed highly dispersive mismatched DNA ensemble in RAD51 but well-converged DNA in DMC1 and RAD51-V273P/D274G. Replacing Loop 1 or Loop 2 residues in DMC1 with RAD51 counterparts enhanced DMC1 fidelity, while reciprocal mutations in RAD51 attenuated its fidelity. Our results show that three Loop 1/Loop 2 residues jointly enact contrasting fidelities of DNA recombinases.

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Structural basis of adhesive binding by desmocollins and desmogleins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1606272113 ◽

2016 ◽

Vol 113 (26) ◽

pp. 7160-7165 ◽

Cited By ~ 74

Author(s):

Oliver J. Harrison ◽

Julia Brasch ◽

Gorka Lasso ◽

Phinikoula S. Katsamba ◽

Goran Ahlsen ◽

...

Keyword(s):

Amino Acids ◽

Crystal Structures ◽

Structural Basis ◽

Cellular Interactions ◽

Opposite Charge ◽

Charged Amino Acids ◽

Structural Framework ◽

Classical Cadherins ◽

Coated Bead

Desmosomes are intercellular adhesive junctions that impart strength to vertebrate tissues. Their dense, ordered intercellular attachments are formed by desmogleins (Dsgs) and desmocollins (Dscs), but the nature of trans-cellular interactions between these specialized cadherins is unclear. Here, using solution biophysics and coated-bead aggregation experiments, we demonstrate family-wise heterophilic specificity: All Dsgs form adhesive dimers with all Dscs, with affinities characteristic of each Dsg:Dsc pair. Crystal structures of ectodomains from Dsg2 and Dsg3 and from Dsc1 and Dsc2 show binding through a strand-swap mechanism similar to that of homophilic classical cadherins. However, conserved charged amino acids inhibit Dsg:Dsg and Dsc:Dsc interactions by same-charge repulsion and promote heterophilic Dsg:Dsc interactions through opposite-charge attraction. These findings show that Dsg:Dsc heterodimers represent the fundamental adhesive unit of desmosomes and provide a structural framework for understanding desmosome assembly.

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Molecular basis for Ras suppressor-1 recruitment to focal adhesions and stabilization of consensus adhesome complex

10.1101/2021.02.19.432017 ◽

2021 ◽

Author(s):

Koichi Fukuda ◽

Fan Lu ◽

Jun Qin

Keyword(s):

Cell Adhesion ◽

Focal Adhesion ◽

Specific Interaction ◽

Tumor Development ◽

Focal Adhesions ◽

Adaptor Protein ◽

Biological Data ◽

Structural Basis ◽

Lim Domain ◽

Insight Into

AbstractRas suppressor-1 (Rsu-1) is a leucine-rich repeat (LRR)-containing protein that is crucial for regulating fundamental cell adhesion processes and tumor development. Rsu-1 interacts with a zinc-finger type multi LIM domain-containing adaptor protein PINCH-1 involved in the integrin-mediated consensus adhesome but not with highly homologous isoform PINCH-2. However, the structural basis for such specific interaction and regulatory mechanism remains unclear. Here, we determined the crystal structures of Rsu-1 and its complex with the PINCH-1 LIM4-5 domains. Rsu-1 displays an arc-shaped solenoid architecture with eight LRRs shielded by the N- and C-terminal capping modules. We show that a large conserved concave surface of the Rsu-1 LRR domain recognizes the PINCH-1 LIM5 domain, and that the C-terminal non-LIM region of PINCH-2 but not PINCH-1 sterically disfavors the Rsu-1 binding. We further show that Rsu-1 can be assembled, via PINCH-1-binding, into a tight hetero-pentamer complex comprising Rsu-1, PINCH-1, ILK, Parvin, and Kindlin-2 that constitute a major consensus integrin adhesome crucial for focal adhesion assembly. Consistently, our mutagenesis and cell biological data consolidate the significance of the Rsu-1/PINCH-1 interaction in focal adhesion assembly and cell spreading. Our results provide a crucial molecular insight into Rsu-1-mediated cell adhesion with implication on how it may regulate tumorigenic growth.

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The synaptonemal complexes of Achlya recurva (Oomycetes): karyotype analysis and three-dimensional reconstruction of pachytene nuclei in antheridia and oogonia

Canadian Journal of Botany ◽

10.1139/b91-178 ◽

1991 ◽

Vol 69 (6) ◽

pp. 1384-1395 ◽

Cited By ~ 2

Author(s):

Hobart R. Williamson ◽

Pesach Ben Yitzchak

Keyword(s):

Synaptonemal Complex ◽

Organizer Region ◽

Nucleolar Organizer Region ◽

Nucleolus Organizer Region ◽

Three Dimensional ◽

Central Element ◽

Three Dimensional Reconstruction ◽

Synaptonemal Complexes ◽

Sequence Of Events ◽

Dimensional Reconstruction

Fifteen synaptonemal complexes, as determined by three-dimensional reconstruction of serial, ultrathin sections, were present within both antheridial and oogonial zygotene and pachytene nuclei of the oomyceteous fungus Achlya recurva, thus n = 15. The present study represents the first complete reconstruction of synaptonemal complexes in the genus Achlya. The occurrence of both zygonema and pachynema was simultaneous in antheridia and oogonia. Pachytene nuclei of antheridia and oogonia are small, 13 μm3 in volume, and the average length of the synaptonemal complexes ranged from 1.9 to 4.4 μm. Lateral elements at zygotene ranged from 1.2 to 4.7 μm. Both ends of each synaptonemal complex were attached randomly to the nuclear envelope, so a bouquet formation was not observed at pachytene. In A. recurva, the dimensions of the synaptonemal complex were as follows: overall width = 270 nm; the lateral elements = 75 nm each in width and the central region = 120 nm. There was no central element and associated transverse filaments, which may be associated with development of alternative reproductive strategies other than amphimixis, as in nematodes. Of the 15 synaptonemal complexes present, only the one carrying the nucleolus organizer region could be clearly identified from one nucleus to the next. The nucleolar organizer region was on the average 0.75 μm from the telomere in both zygotene and pachytene nuclei. There were an average of three recombination nodules in each nucleus. Synaptonemal complexes have been reported in over 80 different species of fungi and related protista. Karyotypic evolution in the oomycetes and fungi may be the result of poly-ploidization, followed by cytogenetic diversification involving aneuploidy and differing degrees of polyploidy. Such a sequence of events could explain the apparent polyphyletic formation of this group. Key words: karyotype, Oomycetes, pachytene, synaptonemal complexes, three-dimensional reconstruction.

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Progression of meiotic recombination requires structural maturation of the central element of the synaptonemal complex

Journal of Cell Science ◽

10.1242/jcs.033233 ◽

2008 ◽

Vol 121 (15) ◽

pp. 2445-2451 ◽

Cited By ~ 69

Author(s):

G. Hamer ◽

H. Wang ◽

E. Bolcun-Filas ◽

H. J. Cooke ◽

R. Benavente ◽

...

Keyword(s):

Synaptonemal Complex ◽

Meiotic Recombination ◽

Central Element

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Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa032 ◽

2020 ◽

Vol 26 (7) ◽

pp. 485-497

Author(s):

Diego Hernández-López ◽

Adriana Geisinger ◽

María Fernanda Trovero ◽

Federico F Santiñaque ◽

Mónica Brauer ◽

...

Keyword(s):

Mouse Model ◽

Central Element ◽

Transcript Level ◽

Primary Ovarian Insufficiency ◽

Primary Amenorrhea ◽

Causative Role ◽

Ovarian Insufficiency ◽

Humanized Mouse Model ◽

Chromosome Synapsis ◽

Human Mutation

Abstract More than 50% of cases of primary ovarian insufficiency (POI) and nonobstructive azoospermia in humans are classified as idiopathic infertility. Meiotic defects may relate to at least some of these cases. Mutations in genes coding for synaptonemal complex (SC) components have been identified in humans, and hypothesized to be causative for the observed infertile phenotype. Mutation SYCE1 c.721C>T (former c.613C>T)—a familial mutation reported in two sisters with primary amenorrhea—was the first such mutation found in an SC central element component-coding gene. Most fundamental mammalian oogenesis events occur during the embryonic phase, and eventual defects are identified many years later, thus leaving few possibilities to study the condition’s etiology and pathogenesis. Aiming to validate an approach to circumvent this difficulty, we have used the CRISPR/Cas9 technology to generate a mouse model with an SYCE1 c.721C>T equivalent genome alteration. We hereby present the characterization of the homozygous mutant mice phenotype, compared to their wild type and heterozygous littermates. Our results strongly support a causative role of this mutation for the POI phenotype in human patients, and the mechanisms involved would relate to defects in homologous chromosome synapsis. No SYCE1 protein was detected in homozygous mutants and Syce1 transcript level was highly diminished, suggesting transcript degradation as the basis of the infertility mechanism. This is the first report on the generation of a humanized mouse model line for the study of an infertility-related human mutation in an SC component-coding gene, thus representing a proof of principle.

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