Structural features of human tracheobronchial mucus glycoprotein

Rose, Mary C.; Voter, William A.; Brown, Caroline; Kaufman, Bernard

doi:10.1042/bj2220371

Cited by 66 publications

(40 citation statements)

References 22 publications

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“…This has been shown for ovine submaxillary mucin, which undergoes a change from an extended filament to a globular form following enzymatic removal of the disaccharide O-glycans (228). Airway mucins typically present as flexible filamentous structures (227,247), which on aggregation form a large interwoven network (227) quite different from the massive ropelike structures characteristic of sheep submaxillary mucin aggregates (50). Thus TR and their attached O-glycans influence the size, shape, and mass of mucins, thereby contributing to the biophysical and biological properties of mucus itself.…”

Section: Muc Protein Backbones: Trsmentioning

confidence: 99%

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Rose

Voynow²

2006

Physiological Reviews

956

892

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This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (≥50% carbohydrate, wt/wt). MUC protein backbones are characterized by numerous tandem repeats that contain proline and are high in serine and/or threonine residues, the sites of O-glycosylation. Secretory and membrane-tethered mucins contribute to mucociliary defense, an innate immune defense system that protects the airways against pathogens and environmental toxins. Inflammatory/immune response mediators and the overproduction of mucus characterize chronic airway diseases: asthma, chronic obstructive pulmonary diseases (COPD), or cystic fibrosis (CF). Specific inflammatory/immune response mediators can activate mucin gene regulation and airway remodeling, including goblet cell hyperplasia (GCH). These processes sustain airway mucin overproduction and contribute to airway obstruction by mucus and therefore to the high morbidity and mortality associated with these diseases. Importantly, mucin overproduction and GCH, although linked, are not synonymous and may follow from different signaling and gene regulatory pathways. In section i, structure, expression, and localization of the 18 human MUC genes and MUC gene products having tandem repeat domains and the specificity and application of MUC-specific antibodies that identify mucin gene products in airway tissues, cells, and secretions are overviewed. Mucin overproduction in chronic airway diseases and secretory cell metaplasia in animal model systems are reviewed in section ii and addressed in disease-specific subsections on asthma, COPD, and CF. Information on regulation of mucin genes by inflammatory/immune response mediators is summarized in section iii. In section iv, deficiencies in understanding the functional roles of mucins at the molecular level are identified as areas for further investigations that will impact on airway health and disease. The underlying premise is that understanding the pathways and processes that lead to mucus overproduction in specific airway diseases will allow circumvention or amelioration of these processes.

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Section: Muc Protein Backbones: Trsmentioning

confidence: 99%

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Rose

Voynow²

2006

Physiological Reviews

956

892

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“…The physical properties of this gel-like secretion are due solely to high molecular weight O-linked glycoproteins termed mucins. Respiratory mucins are polydisperse in mass (M r 2-40 ϫ 10 6 ) and length (0.5-10 m) and can be fragmented into their constituent subunits (M r 2-3 ϫ 10 6 ) by reduction (1)(2)(3)(4)(5)(6). Proteinase treatment of reduced subunits yields high molecular weight glycopeptides (M r 300,000-500,000), and these fragments contain the majority of the O-linked glycans.…”

mentioning

confidence: 99%

Identification of Two Glycoforms of the MUC5B Mucin in Human Respiratory Mucus

Thornton

Howard

Khan³

et al. 1997

Journal of Biological Chemistry

161

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It has been demonstrated previously that respiratory secretions contain three oligomeric, gel-forming mucins; one of these was identified as the product of the MUC5AC gene (1). Here we demonstrate that the other two mucins are glycoforms of the MUC5B gene product. This was accomplished by trypsin treatment of the purified reduced mucin subunit populations and N-terminal sequencing of the liberated peptides. The products of trypsin digestion were separated by gel filtration into high molecular weight mucin glycopeptides and low molecular weight tryptic peptides. The latter were fractionated by reverse phase chromatography, and four of the major peptides were sequenced. Three of these peptides were identical to and contiguous within a 51-amino acid sequence deduced from a cDNA clone (JER57) encoding a portion of the MUC5B mucin. The other peptide is also present within this sequence but showed identity in only 9 of its 10 residues. A polyclonal antiserum raised against one of these peptides was reactive with the two putative MUC5B glycoforms. Analysis of the high molecular weight glycopeptides indicated that the MUC5B subunit contained different types and lengths of glycosylated domains; one domain of M r 7.3 ؋ 10 5 , two domains of M r 5.2 ؋ 10 5, and a third domain of M r 2.0 ؋ 10 5 . The amino acid composition of the larger two glycopeptides was similar in serine, threonine, and proline content but distinct from that of the smallest glycopeptide. Each of these domains in the mucin subunit is separated by a trypsin-sensitive region, and the relative abundance of the major peptides derived by proteolysis of these regions and their occurrence in a contiguous sequence suggest that they contain a common cysteine-rich motif.Respiratory tract mucus is the principal barrier in the lung against chemical and pathological insult. The physical properties of this gel-like secretion are due solely to high molecular weight O-linked glycoproteins termed mucins. Respiratory mucins are polydisperse in mass (M r 2-40 ϫ 10 6 ) and length (0.5-10 m) and can be fragmented into their constituent subunits (M r 2-3 ϫ 10 6

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“…Unless normal tracheobronchial mucin isolated from lavage samples obtained by fiberoptic bronchoscopy is inherently smaller than mucin isolated from expectorated LM-gel samples and from tracheal aspirates, some step in the processing procedure of the lavage fluid likely results in fragmentation of the mucin. It has recently been shown by electron microscopy and molecular sieving studies that sonication of human TBM yields smaller molecules (47). Presumably, the mucin molecules in the lavaged samples (1 1) could be fragmented either by sonication (which procedure was used by Sachdev et al (1 1) to dissolve the lyophilized sample prior to chromatography) or by proteinases released by freezing and thawing of lung cells present in lavaged secretions (48).…”

Section: Discussionmentioning

confidence: 99%

Biochemical Properties of Tracheobronchial Mucins from Cystic Fibrosis and Non-Cystic Fibrosis Individuals

et al. 1987

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ABSTRACT. Tracheobronchial mucins from healthy individuals and from patients with bronchial asthma or cystic fibrosis (CF) were isolated from lung mucus, purified, and their chemical and physical properties compared. Normal and asthmatic mucins required both a dissociating and a reducing agent for solubilization and exhibited identical chromatographic behavior on Sepharose 4B, Sepharose 2B, and hydroxylapatite and similar amino acid and carbohydrate compositions. In contrast, 1) C F lung mucins were solubilized in the absence of dissociating and/or reducing agents and 2) the majority of the C F mucins analyzed was eluted in the included volume of Sepharose 4B with K. , values of 0.3 + 0.1 rather than in the void volume and thus appeared smaller than normal and asthmatic mucins. The lower molecular weight mucins in C F sputum apparently are produced by bacterial or inflammatory cell proteinases since radiolabelled asthmatic mucin was digested to smaller fragments when incubated with crude C F lung mucosal samples. Furthermore, mucins secreted by tracheal explants from C F and from non-CF individuals eluted in the void volume on Sepharose 4B, suggesting that CF tracheobronchial mucins were not inherently smaller than non-CF mucins. (Pediatr Res 22: 545-551, 1987 mucus of exocrine glands or epithelial tubular systems of the respiratory, gastrointestinal, and reproductive tracts (2) which is the basis for the generally held assumption that C F mucus is "abnormal." Since mucus glycoproteins (mucins) are the macromolecules responsible for the viscoelastic properties of mucus (3-5), alterations in mucin structure could effect the physiological behavior of mucus.To date, the most comprehensive studies on C F mucins (6-8) have utilized TBM isolated from C F sputum as copious amounts of such material are readily available. There is limited information available on TBM from healthy airways primarily because of the difficulties in obtaining sufficient amounts of adequate material for analysis. Thus, insufficient information currently exists to determine whether C F and non-CF mucins are different (see Ref. 9 for review) although available studies suggest differences in sulfation of C F respiratory tract mucins (10). However, recent studies have suggested that TBM from healthy airways exhibit physical properties (size, chromatographic behavior on molecular sieving, solubility) different than those of mucins from pathological airways (I I-13). While isolating and purifying human mucins from normal and pathological mucus, we obtained results that indicated that C F TBM were considerably more heterogeneous and smaller in size than non-CF TBM. The smaller size of C F mucins in the samples analyzed could result from in vivo proteolysis, as C F airways are chronically infected with pathogens that produce proteinases (14, 15) and both C F sputum and bronchial washings contain high levels of extracellular proteinase activity (1 6-18). Alternatively, the smaller mucins could reflect inherent differences in C F mucins. These possibili...

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Structural features of human tracheobronchial mucus glycoprotein

Cited by 66 publications

References 22 publications

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Identification of Two Glycoforms of the MUC5B Mucin in Human Respiratory Mucus

Biochemical Properties of Tracheobronchial Mucins from Cystic Fibrosis and Non-Cystic Fibrosis Individuals

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