Bioinorganic Explorations of Zn(II) Sequestration by Human S100 Host-Defense Proteins.
Ontology highlight
ABSTRACT:
SUBMITTER: Cunden LS
PROVIDER: S-EPMC5989567 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
Publications
Bioinorganic Explorations of Zn(II) Sequestration by Human S100 Host-Defense Proteins.
Cunden Lisa S LS Nolan Elizabeth M EM
Biochemistry 20180306 11
The human innate immune system launches a metal-withholding response to starve invading microbial pathogens of essential metal nutrients. Zn(II)-sequestering proteins of the human S100 family contribute to this process and include calprotectin (CP, S100A8/S100A9 oligomer, calgranulin A/B oligomer), S100A12 (calgranulin C), and S100A7 (psoriasin). This Perspective highlights recent advances in the Zn(II) coordination chemistry of these three proteins, as well as select studies that evaluate Zn(II ...[more]
Similar Datasets
Project description:The human innate immune protein calprotectin (CP, S100A8/S100A9 oligomer, calgranulin A/calgranulin B oligomer, MRP-8/MRP-14 oligomer) chelates a number of first-row transition metals, including Mn(II), Fe(II), and Zn(II), and can withhold these essential nutrients from microbes. Here we elucidate the Ni(II) coordination chemistry of human CP. We present a 2.6-Å crystal structure of Ni(II)- and Ca(II)-bound CP, which reveals that CP binds Ni(II) ions at both its transition-metal-binding sites: the His3Asp motif (site 1) and the His6 motif (site 2). Further biochemical studies establish that coordination of Ni(II) at the hexahistidine site is thermodynamically preferred over Zn(II). We also demonstrate that CP can sequester Ni(II) from two human pathogens, Staphylococcus aureus and Klebsiella pneumoniae, that utilize this metal nutrient during infection, and inhibit the activity of the Ni(II)-dependent enzyme urease in bacterial cultures. In total, our findings expand the biological coordination chemistry of Ni(II)-chelating proteins in nature and provide a foundation for evaluating putative roles of CP in Ni(II) homeostasis at the host-microbe interface and beyond.
| S-EPMC5754018 | biostudies-literature
Project description:The calgranulins form a class of S100 proteins in higher vertebrates that innate-immune cells release in abundance at infection sites. These proteins function by binding transition metal ions to prevent microbial pathogens from obtaining those essential nutrients. Mammals express three distinct members of this family: S100A8 (calgranulin A), S100A9 (calgranulin B, which heterooligomerizes with S100A8 to form calprotectin), and S100A12 (calgranulin C), that exhibit Ca(II)-dependent transition metal binding properties. Human calprotectin effectively sequesters Mn(II), Fe(II), Ni(II), and Zn(II), whereas human S100A12 selectively sequesters Zn(II) over these other metal ions. Birds and reptiles express a single calgranulin homologue named MRP126, which we reasoned could have properties more similar to those of either calprotectin or S100A12. Here we present the purification and biophysical characterization of recombinant chicken MRP126 and, to the best of our knowledge, provide the first assessment of the metal binding and antimicrobial properties of an avian MRP126. We show that MRP126 is a homodimer that selectively sequesters Zn(II) and restricts the growth of certain microbes. MRP126 binds Zn(II) at two canonical His3Asp sites. The presence of excess Ca(II) increases the affinity of the His3Asp sites from the low-nanomolar to the low-picomolar range, thereby enhancing antimicrobial activity. Chicken MRP126 also binds additional Zn(II) equivalents with low-nanomolar affinity at two nonconserved dicysteine sites and with high-nanomolar affinity using a histidine-rich C-terminal tail that is a hallmark of this clade of calgranulins. Our results with chicken MRP126 suggest that Ca(II)-dependent Zn(II) sequestration was a role of the last common ancestor of calgranulin proteins, with mammalian calprotectin subsequently evolving a broader metal binding repertoire.
| S-EPMC7031041 | biostudies-literature
Project description:In response to microbial infection, the human host deploys metal-sequestering host-defense proteins, which reduce nutrient availability and thereby inhibit microbial growth and virulence. Calprotectin (CP) is an abundant antimicrobial protein released from neutrophils and epithelial cells at sites of infection. CP sequesters divalent first-row transition metal ions to limit the availability of essential metal nutrients in the extracellular space. While functional and clinical studies of CP have been pursued for decades, advances in our understanding of its biological coordination chemistry, which is central to its role in the host-microbe interaction, have been made in more recent years. In this review, we focus on the coordination chemistry of CP and highlight studies of its metal-binding properties and contributions to the metal-withholding innate immune response. Taken together, these recent studies inform our current model of how CP participates in metal homeostasis and immunity, and they provide a foundation for further investigations of a remarkable metal-chelating protein at the host-microbe interface and beyond.
| S-EPMC6066180 | biostudies-literature
Project description:Proteins in human saliva are thought to modulate bacterial colonization of the oral cavity. Yet, information is sparse on how salivary proteins interact with systemic pathogens that transiently or permanently colonize the oral environment. Staphylococcus aureus is a pathogen that frequently colonizes the oral cavity and can cause respiratory disease in hospitalized patients at risk. Here, we investigated salivary protein binding to this organism upon exposure to saliva as a first step toward understanding the mechanism by which the organism can colonize the oral cavity of vulnerable patients. By using fluorescently labeled saliva and proteomic techniques, we demonstrated selective binding of major salivary components by S. aureus to include DMBT1(gp-340), mucin-7, secretory component, immunoglobulin A, immunoglobulin G, S100-A9, and lysozyme C. Biofilm-grown S. aureus strains bound fewer salivary components than in the planctonic state, particularly less salivary immunoglobulins. A corresponding adhesive component on the S. aureus surface responsible for binding salivary immunoglobulins was identified as staphylococcal protein A (SpA). However, SpA did not mediate binding of nonimmunoglobulin components, including mucin-7, indicating the involvement of additional bacterial surface adhesive components. These findings demonstrate that a limited number of salivary proteins, many of which are associated with various aspects of host defense, selectively bind to S. aureus and lead us to propose a possible role of saliva in colonization of the human mouth by this pathogen.
| S-EPMC3639616 | biostudies-literature
Project description:BACKGROUND: Many characterised proteins contain metal ions, small organic molecules or modified residues. In contrast, the huge amount of data generated by genome projects consists exclusively of sequences with almost no annotation. One of the goals of the structural genomics initiative is to provide representative three-dimensional (3-D) structures for as many protein/domain folds as possible to allow successful homology modelling. However, important functional features such as metal co-ordination or a type of prosthetic group are not always conserved in homologous proteins. So far, the problem of correct annotation of bioinorganic proteins has been largely ignored by the bioinformatics community and information on bioinorganic centres obtained by methods other than crystallography or NMR is only available in literature databases. RESULTS: COMe (Co-Ordination of Metals) represents the ontology for bioinorganic and other small molecule centres in complex proteins. COMe consists of three types of entities: 'bioinorganic motif' (BIM), 'molecule' (MOL), and 'complex proteins' (PRX), with each entity being assigned a unique identifier. A BIM consists of at least one centre (metal atom, inorganic cluster, organic molecule) and two or more endogenous and/or exogenous ligands. BIMs are represented as one-dimensional (1-D) strings and 2-D diagrams. A MOL entity represents a 'small molecule' which, when in complex with one or more polypeptides, forms a functional protein. The PRX entities refer to the functional proteins as well as to separate protein domains and subunits. The complex proteins in COMe are subdivided into three categories: (i) metalloproteins, (ii) organic prosthetic group proteins and (iii) modified amino acid proteins. The data are currently stored in both XML format and a relational database and are available at http://www.ebi.ac.uk/come/. CONCLUSION: COMe provides the classification of proteins according to their 'bioinorganic' features and thus is orthogonal to other classification schemes, such as those based on sequence similarity, 3-D fold, enzyme activity, or biological process. The hierarchical organisation of the controlled vocabulary allows both for annotation and querying at different levels of granularity.
| S-EPMC395836 | biostudies-literature
Project description:The fused-type S100 protein profilaggrin and its proteolytic products including filaggrin are important in the formation of a normal epidermal barrier; however, the specific function of the S100 calcium-binding domain in profilaggrin biology is poorly understood. To explore its molecular function, we determined a 2.2?Å-resolution crystal structure of the N-terminal fused-type S100 domain of human profilaggrin with bound calcium ions. The profilaggrin S100 domain formed a stable dimer, which contained two hydrophobic pockets that provide a molecular interface for protein interactions. Biochemical and molecular approaches demonstrated that three proteins, annexin II/p36, stratifin/14-3-3 sigma, and heat shock protein 27, bind to the N-terminal domain of human profilaggrin; one protein (stratifin) co-localized with profilaggrin in the differentiating granular cell layer of human skin. Together, these findings suggest a model where the profilaggrin N-terminus uses calcium-dependent and calcium-independent protein-protein interactions to regulate its involvement in keratinocyte terminal differentiation and incorporation into the cornified cell envelope.
| S-EPMC4466033 | biostudies-literature
Project description:In humans, the S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable. This family of proteins modulates cellular responses by functioning both as intracellular Ca(2+) sensors and as extracellular factors. Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis and immune evasion. Drug discovery efforts have identified leads for inhibiting several S100 family members, and two of the identified inhibitors have progressed to clinical trials in patients with cancer. This Review highlights new findings regarding the role of S100 family members in cancer diagnosis and treatment, the contribution of S100 signalling to tumour biology, and the discovery and development of S100 inhibitors for treating cancer.
| S-EPMC4369764 | biostudies-literature
Project description:The human genome codes for 21 S100 protein family members, which exhibit cell- and tissue-specific expression patterns. Despite sharing a high degree of sequence and structural similarity, the S100 proteins bind a diverse range of protein targets and contribute to a broad array of intracellular and extracellular functions. Consequently, the S100 proteins regulate multiple cellular processes such as proliferation, migration and/or invasion, and differentiation, and play important roles in a variety of cancers, autoimmune diseases, and chronic inflammatory disorders. This review focuses on the development of S100 neutralizing antibodies and small molecule inhibitors and their potential therapeutic use in controlling disease progression and severity.
| S-EPMC6297089 | biostudies-literature
Project description:The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity.
| S-EPMC3677170 | biostudies-other
Project description:Erythropoietin (EPO) is a clinically significant four-helical cytokine, exhibiting erythropoietic, cytoprotective, immunomodulatory, and cancer-promoting activities. Despite vast knowledge on its signaling pathways and physiological effects, extracellular factors regulating EPO activity remain underexplored. Here we show by surface plasmon resonance spectroscopy, that among eighteen members of Ca2+-binding proteins of the S100 protein family studied, only S100A2, S100A6 and S100P proteins specifically recognize EPO with equilibrium dissociation constants ranging from 81 nM to 0.5 µM. The interactions occur exclusively under calcium excess. Bioinformatics analysis showed that the EPO-S100 interactions could be relevant to progression of neoplastic diseases, including cancer, and other diseases. The detailed knowledge of distinct physiological effects of the EPO-S100 interactions could favor development of more efficient clinical implications of EPO. Summing up our data with previous findings, we conclude that S100 proteins are potentially able to directly affect functional activities of specific members of all families of four-helical cytokines, and cytokines of other structural superfamilies.
| S-EPMC8773746 | biostudies-literature