A5088469727- Sperm and Testicular Function
- Animal Genetics and Reproduction
- Reproductive Biology and Fertility
- Plant Reproductive Biology
- Heat shock proteins research
- Enzyme Structure and Function
- Catalytic C–H Functionalization Methods
- Insect and Arachnid Ecology and Behavior
- Cyclopropane Reaction Mechanisms
- Protein Structure and Dynamics
- Cytomegalovirus and herpesvirus research
- Synthesis and biological activity
- Pediatric Urology and Nephrology Studies
- Asymmetric Synthesis and Catalysis
- Crystal structures of chemical compounds
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Synthetic Organic Chemistry Methods
- Crystallography and molecular interactions
- Proteins in Food Systems
- RNA Interference and Gene Delivery
- Urological Disorders and Treatments
- Metal complexes synthesis and properties
- RNA and protein synthesis mechanisms
- GDF15 and Related Biomarkers
National Institute for Communicable Disease Control and Prevention
2025
Karolinska Institutet
2010-2024
University of York
2024
Yale University
2024
Science for Life Laboratory
2024
Stockholm University
2024
Hull York Medical School
2024
Biomedical Research Institute
2024
Taiyuan University of Technology
2011-2018
Shaanxi Normal University
2014
Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor β (TGF-β) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved tumor angiogenesis preeclampsia. Here, we present crystal structures ectodomain human ENG its complex with ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts a hydrophobic surface N-terminal orphan domain ENG, which adopts new duplicated fold generated by circular permutation. The...
Uromodulin is the most abundant protein in urine. It exclusively produced by renal epithelial cells and it plays key roles kidney function disease. mainly exerts its as an extracellular matrix whose assembly depends on a conserved, specific proteolytic cleavage leading to conformational activation of Zona Pellucida (ZP) polymerisation domain. Through comprehensive approach, including extensive characterisation uromodulin processing cellular models knock-out mice, we demonstrate that...
Recognition between sperm and the egg surface marks beginning of life in all sexually reproducing organisms. This fundamental biological event depends on species-specific interaction rapidly evolving counterpart molecules gametes. We report biochemical, crystallographic, mutational studies domain repeats 1-3 invertebrate coat protein VERL their with cognate lysin. fold like functionally essential N-terminal repeat mammalian receptor ZP2, whose structure is also described here. Whereas...
Significance Urinary tract infection is the most common nonepidemic bacterial in humans, with 150 million cases per year and a global health care cost above $6 billion. Because urinary not protected by mucus, mammals produce molecular net that captures pathogenic bacteria urine clears them from body. By visualizing 3D structure of its building block, glycoprotein uromodulin, we provide insights into how built, it compromised mutations patients kidney diseases. Our work also explains...
Following the fertilization of an egg by a single sperm, coat or zona pellucida (ZP) hardens and polyspermy is irreversibly blocked. These events are associated with cleavage N-terminal region (NTR) glycoprotein ZP2, major subunit ZP filaments. ZP2 processing thought to inactivate sperm binding ZP, but its molecular consequences connection hardening unknown. Biochemical structural studies show that triggers oligomerization. Moreover, structure native vertebrate filament, combined AlphaFold...
A crucial event in sexual reproduction is when haploid sperm and egg fuse to form a new diploid organism at fertilization. In mammals, direct interaction between JUNO IZUMO1 mediates gamete membrane adhesion, yet their role fusion remains enigmatic. We used AlphaFold predict the structure of other extracellular proteins essential for fertilization determine if they could complex that may mediate fusion. first identified TMEM81, whose gene expressed by mouse human spermatids, as protein...
Abstract Mammalian fertilisation begins when sperm interacts with the egg zona pellucida (ZP), whose ZP1 subunit is important for fertility by covalently cross-linking ZP filaments into a three-dimensional matrix. Like ZP4, structurally-related component absent in mouse, predicted to contain an N-terminal ZP-N domain of unknown function. Here we report characterisation proteins carrying mutations from infertile patients, which suggests that, human, filament crucial form stable ZP. We map...
Article16 November 2020Open Access Source DataTransparent process Cryo-EM structure of native human uromodulin, a zona pellucida module polymer Alena Stsiapanava orcid.org/0000-0001-6560-011X Department Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden These authors contributed equally to this work Search for more papers by author Chenrui Xu orcid.org/0000-0002-5605-728X School Biological Sciences, Nanyang Technological University, Singapore, Singapore NTU Institute...
Monoclonal antibody IE-3 prevents mouse fertilization by binding ZP2, a major component of the oocyte-specific zona pellucida (ZP). We show that an IE3-derived single-chain variable fragment (scFV) is sufficient for blocking in vitro and determine structural basis IE-3/ZP2 recognition. The high-affinity this interaction depends on induced fit epitope, offering insights non-hormonal immunocontraceptive design without off-target effects.
We present a strategy to obtain milligrams of highly post-translationally modified eukaryotic proteins, transiently expressed in mammalian cells as rigid or cleavable fusions with mammalianized version bacterial maltose-binding protein (mMBP). This variant was engineered combine mutations that enhance MBP solubility and affinity purification, well provide crystal-packing interactions for increased crystallizability. Using this cell type-independent approach, we could increase the expression...
Abstract An unusual formal [1+4] annulation of α‐dicarbonyl compounds with 1,1‐dicyano‐1,3‐dienes has been realized, leading to facile syntheses cyclopentenimines and cyclopentenones in a unique manner. Mechanistic investigation implies that this reaction takes place through P(NMe 2 ) 3 ‐mediated cyclopropanation followed by base‐catalyzed cyclopropane rearrangement. It therefore represents an unprecedented mode involving Kukhtin–Ramirez adducts.
Glycoprotein 2 (GP2) and uromodulin (UMOD) filaments protect against gastrointestinal urinary tract infections by acting as decoys for bacterial fimbrial lectin FimH. By combining AlphaFold2 predictions with X-ray crystallography cryo-EM, we show that these proteins contain a bipartite decoy module whose new fold presents the high-mannose glycan recognized The structure rationalizes UMOD mutations associated kidney diseases visualizes key epitope implicated in cast nephropathy.
OVGP1 is the major non-serum glycoprotein in oviduct fluid at time of fertilization and early embryo development. Its activity differs among species. Here, we show that C-terminal region recombinant regulates its binding to extracellular zona pellucida affects during fertilization. While porcine penetrates two-thirds thickness pellucida, shorter glycoproteins, including rabbit OVGP1, are restricted outer one-third matrix. Deletion reduces ability penetrate through prevents endocytosis. This...
Abstract An unprecedented and highly efficient tris(dimethylamino)phosphine [P(NMe 2 ) 3 ]‐mediated deoxygenative [4 + 1] annulation of N ‐acyldiazenes with α‐dicarbonyl compounds such as isatins, α‐keto esters, α‐diketones is reported. The reactions proceed smoothly under mild conditions to deliver a broad range 2,2,5‐trisubstituted 1,3,4‐oxadiazole derivatives in moderate excellent yields from readily available starting materials. It represents the first realization [4+1] mode involving...
Mammalian oocytes are enveloped by the zona pellucida (ZP), an extracellular matrix of glycoproteins. In sperm, stimulation with ZP proteins evokes a rapid Ca2+ influx via sperm-specific, pH-sensitive channel CatSper. However, physiological role and molecular mechanisms underlying ZP-dependent activation CatSper unknown. Here, we delineate sequence ZP-signaling events in mouse sperm. We show that evoke intracellular pHi increase rests predominantly on Na+/H+ exchange NHA1 requires cAMP...
A novel P(NMe2)3-mediated formal carbon-halogen bond insertion of isatins into allylic and benzylic bromides/chlorides has been realized, leading to a facile synthesis 3-halo 3,3'-disubstituted oxindoles. This reaction relies on the unique dual nucleophilic-electrophilic reactivity pattern Kukhtin-Ramirez adduct via cascade SN2-SN2 process. It also represents rare metal-free approach for insertion. Upon treatment with trifluoroacetic acid, spirooxindole-γ-butyrolactones have efficiently...
A crucial event in sexual reproduction is when haploid sperm and egg fuse to form a new diploid organism at fertilization. In mammals, direct interaction between JUNO IZUMO1 mediates gamete membrane adhesion, yet their role fusion remains enigmatic. We used AlphaFold predict the structure of other extracellular proteins essential for fertilization determine if they could complex that may mediate fusion. first identified TMEM81, whose gene expressed by mouse human spermatids, as protein...