Role of zinc in female reproduction

Biology of Reproduction, Год журнала: 2021, Номер 104(5), С. 976 - 994

Опубликована: Фев. 17, 2021

Abstract Zinc is a critical component in number of conserved processes that regulate female germ cell growth, fertility, and pregnancy. During follicle development, sufficient intracellular concentration zinc the oocyte maintains meiotic arrest at prophase I until ready to undergo maturation. An adequate supply necessary for form fertilization-competent egg as dietary deficiency or chelation disrupts maturation reduces quality. Following sperm fusion initiate acrosomal reaction, quick release zinc, known spark, induces activation addition facilitating zona pellucida hardening reducing motility prevent polyspermy. Symmetric division, proliferation, differentiation preimplantation embryo rely on availability, both during development post-fertilization. Further, fetal contribution placenta, limb neural tube are hindered females challenged with In this review, we discuss role fertilization, pregnancy focus recent studies mammalian females. We further detail fundamental zinc-mediated reproductive have only been explored non-mammalian species speculate similar mechanisms mammals. The evidence collected over last decade highlights necessity normal fertility healthy outcomes, which suggests supplementation should be considered age women risk deficiency.

Язык: Английский

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Modeling Zinc Complexes Using Neural Networks

Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 64(8), С. 3140 - 3148

Опубликована: Апрель 8, 2024

Understanding the energetic landscapes of large molecules is necessary for study chemical and biological systems. Recently, deep learning has greatly accelerated development models based on quantum chemistry, making it possible to build potential energy surfaces explore space. However, most this work focused organic due simplicity their electronic structures as well availability data sets. In work, we a architecture model energetics zinc organometallic complexes. To achieve this, have compiled configurationally conformationally diverse set complexes using metadynamics overcome limitations traditional sampling methods. terms neural network potentials, our results indicate that complexes, partial charges play an important role in modeling long-range interactions with network. Our developed outperforms semiempirical methods predicting relative conformers, yielding mean absolute error (MAE) 1.32 kcal/mol reference double-hybrid PWPB95 method.

Язык: Английский

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The Molecular Basis for Zinc Bioavailability

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6561 - 6561

Опубликована: Март 31, 2023

Zinc is an essential micronutrient, and its deficiency perhaps the most prevalent least understood worldwide. Recent advances have expanded understanding of zinc’s unique chemistry molecular roles in a vast array critical functions. However, beyond concept zinc absorption, few studies explored basis bioavailability that determines proportion dietary utilized zinc-dependent processes body. The purpose this review to merge concepts biology with focus on determinants luminal availability, transport, utilization.

Язык: Английский

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Zinc finger proteins: guardians of genome stability

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Июль 25, 2024

Zinc finger proteins (ZNF), a unique yet diverse group of proteins, play pivotal roles in fundamental cellular mechanisms including transcription regulation, chromatin remodeling, protein/RNA homeostasis, and DNA repair. Consequently, the mis regulation ZNF can result variety human diseases, ranging from neurodevelopmental disorders to several cancers. Considering promising results damage repair (DDR) inhibition clinic, as therapeutic strategy for patients with homologous recombination (HR) deficiency, identifying other potential targetable DDR emerged vulnerabilities resistant tumor cells is essential, especially when considering burden acquired drug resistance. Importantly, there are growing number studies new ZNFs revealing their significance pathways, highlighting great targets DDR-inhibition therapy. Although, still many uncharacterized ZNF-containing unknown biological function. In this review, we highlight major classes observed functions mammalian cells. We briefly introduce well-known newly discovered describe molecular contributions health disease, cancer. Finally, discuss mechanisms, cancer therapy advances exploiting future disease.

Язык: Английский

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The WRC domain of GRF transcription factors. Structure and DNA recognition

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 4, 2025

Abstract Growth-regulating factors (GRFs) belong to a plant-specific family of transcription which display important roles in plant growth and development. GRF transcriptional activity is finely tuned by regulatory processes involving post-transcriptional silencing exerted miRNA396, protein-protein interactions co-transcriptional regulators known as GRF-interacting (GIFs). In this way, expression target genes modulated highly complex interplay between GRF/GIF isoform diversity patterns along with miR396 GIF gradients throughout tissues. At the protein level, GRFs are composed two conserved domains QLQ WRC less C-terminal trans-activation domain. Whereas mediates GRF-GIF interaction forming SNH found GIFs, has been proposed putative zinc finger domain responsible for DNA recognition nuclear import. However, structural aspects governing remain unknown. work, we applied bioinformatic biophysical analysis comprehensively characterize features that modulate biological function focus on We provide insights into structure explore driving GRFs:DNA formation. These findings offer new how functions GRFs, laying groundwork future studies their structure-function relationship gene regulation development plants.

Язык: Английский

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Conformational dynamics in specialized C₂H₂ zinc finger domains enable zinc‐responsive gene repression in S. pombe

Protein Science, Год журнала: 2025, Номер 34(2)

Опубликована: Янв. 25, 2025

Abstract Loz1 is a zinc‐responsive transcription factor in fission yeast that maintains cellular zinc homeostasis by repressing the expression of genes required for uptake high conditions. Previous deletion analysis found region containing two tandem C 2 H zinc‐fingers and an upstream “accessory domain” rich histidine, lysine, arginine residues to be sufficient zinc‐dependent DNA binding gene repression. Here we report unexpected biophysical properties this pair seemingly classical fingers. Isothermal titration calorimetry NMR spectroscopy reveal distinct events localized spectra complex dynamic behavior spanning time scales from fast 10 −12 –10 −10 slow >10 0 s. Slow exchange due cis‐trans isomerization TGERP linker results doubling many signals protein. Conformational on −3 s timescale throughout first finger distinguishes it second linked weaker affinity zinc. These findings mechanism sensing illuminate how protein's rough free‐energy landscape enables sensing, regulated expression.

Язык: Английский

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Galvanization of Protein–Protein Interactions in a Dynamic Zinc Interactome

Trends in Biochemical Sciences, Год журнала: 2020, Номер 46(1), С. 64 - 79

Опубликована: Сен. 18, 2020

Presence of Zn2+ at protein–protein interfaces modulates complex stability, protease resistance, introduces structural flexibility, spatial complexity, chemical selectivity, and, above all, reversibility driven in Zn2+-dependent manner.Zinc homeostasis is strictly regulated the cellular level; thus ZPPI formation and dissociation tightly interwoven with status. Factors influencing stability obey covalent bond formation, allosteric modulation, metal-coupled folding, proton-coupled assembly mechanisms, post-translational modifications.Intersystemic zinc network communication reveals terra incognita Zn2+-involved interactions.Difficulties prediction interprotein sites need to be overcome by functional biochemical investigation. Combination labile Zn2+, proteome, global gene expression investigation supported mass spectrometry fluorescence-based studies numerous cell types will allow new ZPPIs identified. The presence function, flexibility/complexity, a manner. Recent have demonstrated that dynamically changing affects processes, including protein assembly. How interactions (ZPPIs) are formed dissociate how their reactivity interactome remain poorly understood, mostly due experimental obstacles. Here, we review recent research advances on role sites, architecture, stability. Moreover, underline importance networks intersystemic highlight bioinformatic challenges required for identification ZPPIs. A complete picture (PPIs), also known as (see Glossary), crucial understand molecular machinery system biology level [1.Fessenden M. Protein maps chart causes disease.Nature. 2017; 549: 293-295Crossref PubMed Scopus (5) Google Scholar, 2.Lasso G. et al.A structure-informed atlas human-virus interactions.Cell. 2019; 178: 1526-1541Abstract Full Text PDF (15) 3.Luck K. reference map human binary interactome.Nature. 2020; 580: 402-408Crossref (23) Scholar]. Identification complexes requires description various aspects, such composition, component affinity, lifetime series physicochemical properties describing interface between proteins. Considering both affinity proteins interact, obligate nonobligate can found, where latter divided into permanent (mostly strong, irreversible) transient (reversible, frequently medium affinity). Transient characterized smaller interfaces, dependent specific recognition patterns, limited surface meets requirement constituents fold exist independently without aggregation [4.Mintseris J. Weng Z. Atomic contact vectors protein-protein recognition.Proteins. 2003; 53: 629-639Crossref (98) Scholar,5.Perkins J.R. al.Transient interactions: structural, functional, properties.Structure. 2010; 18: 1233-1243Abstract (288) Their contain more residues higher polarity stabilized salt bridges hydrogen bonds chain turns gain flexibility [6.Lo Conte L. al.The atomic structure sites.J. Mol. Biol. 1999; 285: 2177-2198Crossref (1679) 7.De S. al.Interaction preferences across obligatory non-obligatory components different.BMC Struct. 2005; 5: 15Crossref (0) 8.Park S.H. al.Prediction interaction using association rule based classification.BMC Bioinform. 2009; 10: 36Crossref (43) specificity elevated utilization same multiple evolution, local environment has been affecting fast adaptation mutations [9.Mintseris Structure, evolution interactions.Proc. Natl. Acad. Sci. U. A. 102: 10930-10935Crossref Scholar,10.Pereira-Leal J.B. al.Evolution duplication homomeric interactions.Genome 2007; 8: R51Crossref (133) Within widely examined PPI network, there an additional small consider. Besides its almost negligible size compared macromolecule diameter, metal ions critical impact structure, complexes. Even though influence living organisms investigated decades, employment PPIs still vague. able utilize smallest available handling PPIs? Some answers derive from consideration d-block ions' ionization potentials, ionic radii, or d-shell electronic configurations, which type groups participate binding [11.Krężel Maret W. Biological inorganic chemistry ions.Arch. Biochem. Biophys. 2016; 611: 3-19Crossref preference ion arrangement amino acid side (coordination sphere). Interfaces metal-involved areas usually stable structures when bound. Such provide quick response perturbations changes during signaling regulatory processes enabling, example, messengers reach target [12.Stein al.Dynamic networks: structured view.FEBS 276: 5390-5405Crossref (77) It may explain frequent involvement Ca2+ pathways ability form break readily, essential respond quickly, interconnected high needed [13.Maret Zinc regulation: nature significance "zinc signals".Int. 2285Crossref (60) 14.Woodier al.Intracellular cardiac ryanodine receptor-mediated calcium release.J. Chem. 2015; 290: 17599-17610Abstract 15.Wessels I. al.Zinc gatekeeper immune function.Nutrients. 9: 1286Crossref (89) confers specificity, since needs spatiotemporal orchestration subunits concentration [16.Kocyła al.Interdependence free – insights signal regulation.Metallomics. 2018; 120-131Crossref environmental sensed PPI, net outcome redox potential, pH, modifications, competitive ligands, etc. Scholar,17.Maret Li Y. Coordination dynamics proteins.Chem. Rev. 109: 4682-4707Crossref 18.Padjasek al.Structural shaped greater works: structure-function relations classical fingers, hook clasp domains.J. Inorg. 204110955Crossref (3) 19.Song al.Metals interfaces.Annu. 2014; 43: 409-431Crossref (35) Among all biologically ions, interacts specifically largest number (~10% encoded genome), defines proteome [20.Andreini C. al.Counting zinc-proteins genome.J. Proteome Res. 2006; 196-201Crossref (547) Its functions, led discovery catalytic hydrolases but utilized source just started evolve [17.Maret Scholar,21.Kochańczyk T. al.Relationship architecture coordination regulations.Metallomics. 7: 244-257Crossref Scholar,22.Auld D.S. sphere sites.BioMetals. 2001; 14: 271-313Crossref (519) Scholar] emerged [18.Padjasek Scholar,23.Kluska al.Metal properties, fingers.Coord. 367: 18-64Crossref (30) What makes it so special harnessing PPI? In answering question, one should consider relative abundance availability under physiological conditions along [24.Outten C.E. O'Halloran T.V. Femtomolar sensitivity metalloregulatory controlling homeostasis.Science. 292: 2488-2492Crossref (1035) Chemically, only switch ligand geometry major energetic disfavor substantial rise filled leading lack field stabilization. oxygen, nitrogen, sulfur donors contributes modulation number, moderate Lewis character demonstrated. Associated geometrical then elevated, especially useful interfaces. maintained diverse substitution kinetics depends metal-to-protein composition first second exchange rates seconds years fact thermodynamically kinetically inert labile, intermediate ternary formed, accelerating rate further transfer [25.Heinz al.On competition zinc.J. 280: 3197-3207Abstract mode action regulation. On hand, results particular utility assemble, other interplay governed (Box 1). proteins, nucleic acids, peptides (including glutathione), chelators cargos, vitamins, carboxylic vast organic compounds products/intermediates metabolism. Integral parts anions (e.g., Pi, HCO3–, HS–, SO42–, Cl–), either larger outcompete forming low weight (LMWL) Scholar,26.Auld ins outs biological sites.Biometals. 22: 141-148Crossref (54) Both LMWLs previously-listed non-protein pool, contains some metallothioneins Rapidly exchanging pool species function together transfer, modulating molecules, playing distinct intra- intercellular Scholar,13.Maret variety molecules brings us definition term 'zinc interactome' species, macromolecules LMWL. Due heterogeneous kinetic thermodynamic character, dynamic 'organism' permeate each other.Box 1Properties Cellular PoolThe steady-state intracellular ([Zn2+]i) must tight control prevent miss-metalation. To do so, homeostatic keeps within (buffered) concentrations act upon Irving-Williams ranks propensity undergo ligands. Intracellular availabilities selectively bind cognate according energies Scholar,75.Osman D. al.Bacterial sensors define correct enzyme metalation.Nat. 15: 241-249Crossref Uncontrolled access would render many metalloproteins dysfunctional likely turn death pathways. One way eukaryotic solved problem compartmentalization, membrane plays fence separate different set transporters gates flow (Figure I) [76.Hara al.Physiological roles transporters: genetic homeostasis.J. Physiol. 67: 283-301Crossref (119) compartmentalization manifested vesicles insulin-storing granules zincosomes placement organelles, released demand [77.Vinkenborg J.L. al.Imaging real time genetically-encoded FRET sensors.Nat. Methods. 6: 737-740Crossref fact, [Zn2+]i buffered range nanomolar picomolar, several orders magnitude lower comparison total 0.1–0.3 mM key player specialized buffering metallothionein, up seven picomolar [78.Krężel Dual Zn(II) metallothionein.J. Am. Soc. 129: 10911-10921Crossref (207) Scholar,79.Krężel functions metamorphic copper metabolism.Int. 1237Crossref machine was found insufficient mechanistically describe model cytosolic match time-dependent (zinc transients). Therefore, muffling introduced time-dependent, combined effect flux, coined initially damping Ca2+, Mg2+, protons [37.Colvin R.A. al.Cytosolic muffling: homeostasis.Metallomics. 2: 306-317Crossref Muffling reactions involve surplus shuttling subcellular stores, and/or removing cell, order restore original value augment capacity Scholar,80.Maret Krężel metallothionien/thionein health disease.Mol. Med. 13: 371-375Crossref As fluorescent Zn2+-specific probes appeared, subnanomolar values were confirmed (erythrocytes, cardiomyocytes, cortical neurons) lines (INS-1, HeLa, HEK293, MCF-7, TamR), summarized Table S1 supplemental information online). Subcellular compartments granules, ER, Golgi, mitochondria seem [81.Qin al.Measuring reticulum Golgi genetically sensors.Proc. 2011; 108: 7351-7356Crossref Scholar,82.Hessels A.M. al.Monitoring ER stimulated breast cancer cells sensors.Metallomics. 211-217Crossref Evaluation extracellular indicates submicromolar range, being consistent storage protein, albumin, [83.Chun H. al.An histidine-containing motif transporter ZIP4 sensing zinc-induced endocytosis mammalian cells.J. 294: 2815-2826Abstract Taking account increasing structurally identified experimentally captured interactions, here explore this unchartered territory present comprehensive outlook state knowledge occurring interactome. This includes screening database factors governing Zn2+-mediated PPIs. Reasonably good sources deposited structures, although, applied crystallization preparation, majority them artificial. More detailed regarding selection online. confirm functionality potential ZPPIs, complementary route verification performed avoid misclassification. literature supplies examples described perspectives 2). Thus, study needed. Complete systematic attempts collect Zn2+-binding considered over years, MetalPDB ZincBind inspected criteria [27.Putignano V. al.MetalPDB 2018: structures.Nucleic Acid. 46: D459-D464Crossref Scholar,28.Ireland S.M. Martin A.C.R. sites.Database (Oxford). 2019baz006Crossref (4) sites; however, disadvantage asymmetric units not assemblies. solves obstacle utilizing assemblies; nevertheless, none databases allows sites. obstacles encountered analyze available, Research Collaboratory Structural Bioinformatics Data Bank (RCSB PDB), assemblies structures. Based procedure here, 165 X-ray NMR PDB derived potentially (Table S2 Figures online), agreement previous estimation [19.Song Importantly, our goal select representative selected treated highly numerically. analysis presented detail section result, Figure 1 presents timeline deposition, organismal distribution, mode, assignment. upward trend Zn2+-containing last 20 noticeable, although per year undergoes fluctuations 1A). distribution organism follows general RCSB corresponds interest rather than 1B). most common four (~94%), followed five (~4%), six (~1%). terms involved site, prevalent Cys4, followe

Язык: Английский

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SARS-CoV-2 spike binding to ACE2 is stronger and longer ranged due to glycan interaction

Biophysical Journal, Год журнала: 2021, Номер 121(1), С. 79 - 90

Опубликована: Дек. 7, 2021

Highly detailed steered molecular dynamics simulations are performed on differently glycosylated receptor binding domains of the severe acute respiratory syndrome coronavirus-2 spike protein. The strength and range increase with glycosylation. interaction energy rises very quickly when pulling proteins apart only slowly drops at larger distances. We see a catch-slip-type behavior whereby interactions during break taken over by new forming. dominant mode is hydrogen bonds, but Lennard-Jones electrostatic relevant as well.

Язык: Английский

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p53 and Zinc: A Malleable Relationship

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Апрель 13, 2022

A large percentage of transcription factors require zinc to bind DNA. In this review, we discuss what makes p53 unique among zinc-dependent factors. The conformation is unusually malleable: binds extremely tightly when folded, but intrinsically unstable in the absence at 37°C. Whether wild-type protein folds cell largely determined by concentration available zinc. Consequently, dysregulation as well a tumorigenic mutations can cause lose zinc, misfold, and forfeit its tumor suppressing activity. We highlight p53’s noteworthy biophysical properties that give rise malleability how proper binding be restored synthetic metallochaperones reactivate mutant p53. activity mechanism are compared those other p53-targeted drugs with an emphasis on have reached clinical trial stage.

Язык: Английский

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GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

Science Immunology, Год журнала: 2022, Номер 7(77)

Опубликована: Ноя. 18, 2022

Herpes simplex virus 1 (HSV-1) infects several billion people worldwide and can cause life-threatening herpes encephalitis (HSE) in some patients. Monogenic defects components of the type I interferon system have been identified patients with HSE, emphasizing role inborn errors immunity underlying HSE pathogenesis. Here, we identify compound heterozygous loss-of-function mutations gene GTF3A encoding for transcription factor IIIA (TFIIIA), a component RNA polymerase III complex, patient common variable immunodeficiency HSE. Patient fibroblasts gene-edited cells displayed impaired HSV-1-induced innate immune responses enhanced HSV-1 replication. Chromatin immunoprecipitation sequencing analysis 5S ribosomal pseudogene 141 (RNA5SP141), an endogenous ligand sensor RIG-I, as transcriptional target TFIIIA. mutant exhibited diminished RNA5SP141 expression abrogated RIG-I activation upon infection. Our work unveils crucial TFIIIA regulation cellular agonist shows that genetic lead to cell-intrinsic anti-HSV-1 predispose

Язык: Английский

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