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Biomacromolecules Apr 2019Binding of small molecules to mucus membranes in the body has an important role in human health, as it can affect the diffusivity and activity of any molecule that acts...
Binding of small molecules to mucus membranes in the body has an important role in human health, as it can affect the diffusivity and activity of any molecule that acts in a mucosal environment. The binding of drugs and of toxins and signaling molecules from mucosal pathogens is of particular clinical interest. Despite the importance of mucus-small molecule binding, there is a lack of data revealing the precise chemical features of small molecules that lead to mucus binding. We developed a novel equilibrium dialysis assay to measure the binding of libraries of small molecules to mucin and other mucus components, substantially increasing the throughput of small molecule binding measurements. We validated the biological relevance of our approach by quantifying binding of the antibiotic colistin to mucin, and showing that this binding was associated with inhibition of colistin's bioactivity. We next used a small molecule microarray to identify 2,4-diaminopyrimidine as a mucin binding motif and confirmed the importance of this motif for mucin binding using equilibrium dialysis. Furthermore, we showed that, for molecules with this motif, binding to mucins and the mucus-associated biopolymers DNA and alginate is modulated by differences in hydrophobicity and charge. Finally, we showed that molecules lacking the motif exhibited different binding trends from those containing the motif. These results open up the prospect of routine testing of small molecule binding to mucus and optimization of drugs for clinically relevant mucus binding properties.
Topics: Amino Acid Motifs; Animals; DNA; Humans; Hydrophobic and Hydrophilic Interactions; Mucins; Mucous Membrane
PubMed: 30779551
DOI: 10.1021/acs.biomac.8b01467 -
G3 (Bethesda, Md.) Jul 2022Epithelia exposed to elements of the environment are protected by a mucus barrier in mammals. This barrier also serves to lubricate during organ movements and to mediate...
Epithelia exposed to elements of the environment are protected by a mucus barrier in mammals. This barrier also serves to lubricate during organ movements and to mediate substance exchanges between the environmental milieu and internal organs. A major component of the mucus barrier is a class of glycosylated proteins called Mucin. Mucin and mucin-related proteins are widely present in the animal kingdom. Mucin mis-regulation has been reported in many diseases such as cancers and ones involving the digestive and respiratory tracts. Although the biophysical properties of isolated Mucins have been extensively studied, in vivo models remain scarce for the study of their functions and regulations. Here, we characterize the Mucin-like JiangShi protein and its mutations in the fruit fly Drosophila. JiangShi is an extracellular glycoprotein with domain features reminiscent of mammalian nonmembranous Mucins, and one of the most widely distributed Mucin-like proteins studied in Drosophila. Both loss and over-production of JiangShi lead to terminal defects in adult structures and organismal death. Although the physiological function of JiangShi remains poorly defined, we present a genetically tractable model system for the in vivo studies of Mucin-like molecules.
Topics: Animals; Drosophila; Glycoproteins; Glycosylation; Mammals; Mucins; Respiratory System
PubMed: 35595239
DOI: 10.1093/g3journal/jkac126 -
Glycobiology Sep 2013Mucin-type O-glycans are the primary constituents of mucins that are expressed on various mucosal sites of the body, especially the bacteria-laden intestinal tract.... (Review)
Review
Mucin-type O-glycans are the primary constituents of mucins that are expressed on various mucosal sites of the body, especially the bacteria-laden intestinal tract. Mucins are the main components of mucus, which is secreted by goblet cells and forms a protective homeostatic barrier between the resident microbiota and the underlying immune cells in the colon. However, the specific role of mucin-type O-glycans in mucus barrier function has been uncertain. Recent studies utilizing mice deficient in key glycosyltransferases involved in O-glycan biosynthesis on intestinal mucins have underscored the importance of mucin-type O-glycosylation in mucus barrier function. This review will highlight recent advances in our understanding of mucin-type O-glycan function in the mucus barrier and how they promote mutualism with our resident microbiota.
Topics: Homeostasis; Humans; Intestinal Mucosa; Intestines; Mucins; Polysaccharides
PubMed: 23752712
DOI: 10.1093/glycob/cwt045 -
Cell Oct 2020The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by...
The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here, we present an integrated structural analysis of the intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryo-electron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi apparatus. Remarkably, a densely O-glycosylated mucin domain performs an organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation.
Topics: Amino Acid Sequence; Animals; Biopolymers; Cryoelectron Microscopy; Disulfides; Female; Glycosylation; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Mice, Inbred C57BL; Models, Molecular; Mucins; Peptides; Protein Domains; Protein Multimerization; von Willebrand Factor
PubMed: 33031746
DOI: 10.1016/j.cell.2020.09.021 -
Advances in Cancer Research 2023Mucin-domain glycoproteins are highly O-glycosylated cell surface and secreted proteins that serve as both biochemical and biophysical modulators. Aberrant expression... (Review)
Review
Mucin-domain glycoproteins are highly O-glycosylated cell surface and secreted proteins that serve as both biochemical and biophysical modulators. Aberrant expression and glycosylation of mucins are known hallmarks in numerous malignancies, yet mucin-domain glycoproteins remain enigmatic in the broad landscape of cancer glycobiology. Here we review the multifaceted roles of mucins in cancer through the lens of the analytical and biochemical methods used to study them. We also describe a collection of emerging tools that are specifically equipped to characterize mucin-domain glycoproteins in complex biological backgrounds. These approaches are poised to further elucidate how mucin biology can be understood and subsequently targeted for the next generation of cancer therapeutics.
Topics: Humans; Mucins; Glycoproteins; Neoplasms; Glycosylation
PubMed: 36725114
DOI: 10.1016/bs.acr.2022.09.001 -
The Ocular Surface Jan 2010Mucins are major components in mucus secretions and apical cell membranes on wet-surfaced epithelia. Structurally, they are characterized by the presence of tandem... (Review)
Review
Mucins are major components in mucus secretions and apical cell membranes on wet-surfaced epithelia. Structurally, they are characterized by the presence of tandem repeat domains containing heavily O-glycosylated serine and threonine residues. O-glycans contribute to maintaining the highly extended and rigid structure of mucins, conferring to them specific physical and biological properties essential for their protective functions. at the ocular surface epithelia, mucin-type O-glycan chains are short and predominantly sialylated, perhaps reflecting specific requirements of the ocular surface. Traditionally, secreted mucins and their O-glycans in the tear film have been involved in the clearance of debris and pathogens from the surface of the eye. New evidence, however, shows that O-glycans on the cell-surface glycocalyx have additional biological roles in the protection of corneal and conjunctival epithelia, such as preventing bacterial adhesion, promoting boundary lubrication, and maintaining the epithelial barrier function through their interaction with galectin-3. Abnormalities in mucin-type O-glycosylation have been identified in many disorders where the stability of the ocular surface is compromised. This review summarizes recent advances in understanding the structure, biosynthesis, and function of mucin-type O-glycans at the ocular surface and their alteration in ocular surface disease.
Topics: Animals; Eye; Eye Diseases; Humans; Mucins; Tears
PubMed: 20105403
DOI: 10.1016/s1542-0124(12)70213-6 -
Current Opinion in Structural Biology Apr 2023Contrary to first appearances, mucus structural biology is not an oxymoron. Though mucus hydrogels derive their characteristics largely from intrinsically disordered,... (Review)
Review
Contrary to first appearances, mucus structural biology is not an oxymoron. Though mucus hydrogels derive their characteristics largely from intrinsically disordered, heavily glycosylated polypeptide segments, the secreted mucin glycoproteins that constitute mucus undergo an orderly assembly process controlled by folded domains at their termini. Recent structural studies revealed how mucin complexes promote disulphide-mediated polymerization to produce the mucus gel scaffold. Additional protein-protein and protein-glycan interactions likely tune the mesoscale properties, stability, and activities of mucins. Evidence is emerging that even intrinsically disordered glycosylated segments have specific structural roles in the production and properties of mucus. Though soft-matter biophysical approaches to understanding mucus remain highly relevant, high-resolution structural studies of mucins and other mucus components are providing new perspectives on these vital, protective hydrogels.
Topics: Mucins; Mucus; Glycoproteins; Polysaccharides; Glycosylation
PubMed: 36753925
DOI: 10.1016/j.sbi.2022.102524 -
World Journal of Gastroenterology Oct 2010Differentiated adenocarcinoma of the stomach is classified into gastric or intestinal phenotypes based on mucus expression. Recent advances in mucin histochemistry and...
Differentiated adenocarcinoma of the stomach is classified into gastric or intestinal phenotypes based on mucus expression. Recent advances in mucin histochemistry and immunohistochemistry have highlighted the importance of such a distinction, and it is important clinically to distinguish between gastric- and intestinal-type differentiated adenocarcinoma. However, a clinical and pathological diagnosis of this type is often difficult in early gastric cancer because of histological similarities between a hyperplastic epithelium and low-grade atypia. Furthermore, determining tumor margins is often difficult, even with extensive preoperative examination. It is therefore critical to consider these diagnostic difficulties and different biological behaviors with high malignant potential when treating patients with gastric-type differentiated adenocarcinoma.
Topics: Adenocarcinoma; Diagnosis, Differential; Humans; Mucins; Phenotype; Stomach Neoplasms
PubMed: 20872962
DOI: 10.3748/wjg.v16.i37.4634 -
Cancer Metastasis Reviews Sep 2020A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called... (Review)
Review
A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called mucins. Mucins, broadly grouped into transmembrane and secreted mucins, are the first responders to any mechanical or chemical insult to the epithelia and help maintain tissue homeostasis. However, their intrinsic properties to protect and repair the epithelia are exploited during oncogenic processes, where mucins are metamorphosed to aid the tumor cells in their malignant journey. Diverse domains, like the variable number tandem repeats (VNTR), sea urchin sperm protein enterokinase and agrin (SEA), adhesion-associated domain (AMOP), nidogen-like domain (NIDO), epidermal growth factor-like domain (EGF), and von Willebrand factor type D domain (vWD) on mucins, including MUC1, MUC4, MUC5AC, MUC5B, and MUC16, have been shown to facilitate cell-to-cell and cell-to-matrix interactions, and cell-autonomous signaling to promote tumorigenesis and distant dissemination of tumor cells. Several obstacles have limited the study of mucins, including technical difficulties in working with these huge glycoproteins, the dearth of scientific tools, and lack of animal models; thus, the tissue-dependent and domain-specific roles of mucins during mucosal protection, chronic inflammation, tumorigenesis, and hematological dissemination of malignant cells are still unclear. Future studies should try to integrate information on the rheological, molecular, and biological characteristics of mucins to comprehensively delineate their pathophysiological role and evaluate their suitability as targets in future diagnostic and therapeutic strategies.
Topics: Animals; Humans; Mucins; Neoplasm Metastasis; Neoplasms; Protein Domains
PubMed: 32488403
DOI: 10.1007/s10555-020-09896-5 -
Trends in Biochemical Sciences Apr 2010Mucins are high molecular weight glycoproteins that are involved in regulating diverse cellular activities both in normal and pathological conditions. Mucin activity and... (Review)
Review
Mucins are high molecular weight glycoproteins that are involved in regulating diverse cellular activities both in normal and pathological conditions. Mucin activity and localization is mediated by several molecular mechanisms, including discrete interactions with other proteins. An understanding of the biochemistry behind the known interactions between mucins and other proteins, coupled with an appreciation of their pathophysiological significance, can lend insight into the development of novel therapeutic agents. Indeed, a recent study demonstrated that a cell permeable inhibitor, PMIP, that disrupts the MUC1-EGFR interaction, is effective in killing breast cancer cells in vitro and in tumor models.
Topics: Humans; Mucins; Neoplasms; Protein Binding; Protein Structure, Tertiary; Transcription Factors; Wnt Proteins
PubMed: 19913432
DOI: 10.1016/j.tibs.2009.10.003