Liquid-crystalline order in mucus

Viney, Christopher; Huber, Anne E.; Verdugo, Pedro

doi:10.1021/ma00056a044

Cited by 55 publications

(56 citation statements)

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“…These interactions could stabilize mucin entanglements or even link mucin oligomers alongside most of their contour lengths (i.e., through a zipper-like mechanism). If so, the asymmetry of the mucin macromolecules would lead to the formation of anisotropic networks (27). In addition, Ca 2ϩ could bind other glycoproteins and anionic proteins to the nascent mucin matrix.…”

Section: Gel-forming Mucins: Structural Changes During Biosynthesis Amentioning

confidence: 99%

Mucin Granule Intraluminal Organization

Pérez-Vilar

2007

Am J Respir Cell Mol Biol

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Mucus secretions have played a central role in the evolution of multicellular organisms, enabling adaptation to widely differing environments. In vertebrates, mucus covers and protects the epithelial cells in the respiratory, gastrointestinal, urogenital, visual, and auditory systems, amphibian's epidermis, and the gills in fishes. Deregulation of mucus production and/or composition has important consequences for human health. For example, mucus obstruction of small airways is observed in chronic airway diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The major protein component in the mucus is a family of large, disulfide-bonded glycoproteins known as gel-forming mucins. These proteins are accumulated in large, regulated secretory granules (the mucin granules) that occupy most of the apical cytoplasm of specialized cells known as mucous/goblet cells. Since mucin oligomers have contour dimensions larger than the mucin granule average diameter, the question arises how these highly hydrophilic macromolecules are organized within these organelles. I review here the intraluminal organization of the mucin granule in view of our knowledge on the structure, biosynthesis, and biophysical properties of gel-forming mucins, and novel imaging studies in living mucous/goblet cells. The emerging concept is that the mucin granule lumen comprises a partially condensed matrix meshwork embedded in a fluid phase where proteins slowly diffuse.Keywords: granule matrix; mucin granules; mucins; secretory granules; secretion GEL-FORMING MUCINS: STRUCTURE AND BIOSYNTHESISFive gel-forming mucins (MUC2, MUC5AC, MUC5B, MUC6, and MUC19) have been found in humans. These mucins share a similar structural organization ( Figure 1A) characterized by (1, 2): (i ) multi-domain polypeptide chains with thousands of amino acid residues; (ii) a large, centrally located region mainly consisting of threonine and/or serine-rich tandemly repeated sequences to which O-linked oligosaccharides are covalently bound; (iii) the presence of several under-glycosylated, Cys-rich domains that are conserved among different mucins; (iv) the formation of disulfide-linked species ranging from dimers to more than 16 oligomers (3); and (v ) molecular polydispersity because of genetic polymorphism (e.g., multiple alleles encoding

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Section: Gel-forming Mucins: Structural Changes During Biosynthesis Amentioning

confidence: 99%

Mucin Granule Intraluminal Organization

Pérez-Vilar

2007

Am J Respir Cell Mol Biol

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“…In considering the mucin as a polymer, Verdugo et al (17) have suggested that mucins in the granule matrix must be folded in a non-random conformation. Polarized microscopy images of partially hydrated mucus granules demonstrate that even at visible wavelengths, it is possible to observe the signature of nematic crystalline structures in mucus, which reveals the presence of large-scale supramolecular organization (19).…”

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confidence: 99%

Unpacking a gel-forming mucin: a view of MUC5B organization after granular release

Kesımer¹,

Makhov

Griffith

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Kesimer M, Makhov AM, Griffith JD, Verdugo P, Sheehan JK. Unpacking a gel-forming mucin: a view of MUC5B organization after granular release. Am J Physiol Lung Cell Mol Physiol 298: L15-L22, 2010. First published September 25, 2009 doi:10.1152/ajplung.00194.2009.-Gel-forming mucins are the largest complex glycoprotein macromolecules in the body. They form the matrix of gels protecting all the surface epithelia and are secreted as disulfide-bonded polymeric structures. The mechanisms by which they are formed and organized within cells and thereafter released to form mucus gels are not understood. In particular, the initial rate of expansion of the mucins after release from their secretory granules is very rapid (seconds), but no clear mechanism for how it is achieved has emerged. Our major interest is in lung mucins, but most particularly in MUC5B, which is the major gel-forming mucin in mucus, and which provides its major protective matrix. In this study, using OptiPrep density gradient ultracentrifugation, we have isolated a small amount of a stable form of the recently secreted and expanding MUC5B mucin, which accounts for less than 2% of the total mucin present. It has an average mass of ϳ150 ϫ 10 6 Da and size Rg of 150 nm in radius of gyration. In transmission electron microscopy, this compact mucin has maintained a circular structure that is characterized by flexible chains connected around protein-rich nodes as determined by their ability to bind colloidal gold. The appearance indicates that the assembled mucins in a single granular form are organized around a number of nodes, each attached to four to eight subunits. The organization of the mucins in this manner is consistent with efficient packing of a number of large heavily glycosylated monomers while still permitting their rapid unfolding and hydration. For the first time, this provides some insight into how the carbohydrate regions might be organized around the NH2-and COOH-terminal globular protein domains within the granule and also explains how the mucin can expand so rapidly upon its release. mucin granule; secretion; mucus MUCINS ARE LARGE COMPLEX GLYCOPROTEIN macromolecules that provide the basis of gels protecting the surface epithelia in many multicellular organisms. In humans, these macromolecules come in two major kinds, the epithelial or transmembrane mucins characterized by COOH-terminal domains that attach to cell surface membranes (5) and those termed the gel-forming mucins that are secreted as highly assembled polymeric structures (14). There are four such molecules, MUC2, MUC5AC, MUC5B, and MUC6, and they form the largest glycoproteins in the body (10). The functions of these molecules are understood in general terms, i.e., they form the basic infrastructure of the epithelial protective gels, but the mechanisms by which they are made and organized within cells and thereafter released are not understood.The basis of the polymeric assembly of these large mucin glycoproteins is thought to mimic that of another related glycoprotein calle...

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“…Mucin is known to display liquid crystallinelike behavior, 17 from which it follows that adsorbed thin films are very likely to be birefringent. Hence it seems to be essential to properly consider the anisotropy of self-assembled mucin thin films, unlike the "simple" protein layers that are merely and sufficiently characterized by the number of adsorbed molecules per unit area.…”

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Structural hysteresis and hierarchy in adsorbed glycoproteins

Horváth

Yakubov

Ramsden

2008

The Journal of Chemical Physics

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The adsorption and desorption of the giant heavily glycosylated protein mucin from solutions of different bulk concentrations have been followed at the nanometer scale using high resolution molecular microscopy based on optical waveguide lightmode spectroscopy. Modeling the layer as a uniaxial thin film allowed the in situ determination of adsorbed mass, mean layer thickness, and structural anisotropy. These parameters manifest highly significant adsorption-desorption hysteresis, indicating at least two dominant glycoprotein conformational types (i.e., molecular states, structurally and kinetically distinguishable). One of them is proposed to be a conformationally extended state that engenders uniaxial symmetry and dominates layers generated from low bulk concentrations. The revealed structure and the mechanism by which it is formed are postulated to be a general feature of the self-assembly of large glycoproteins. We expect that, inter alia, this knowledge will be relevant for understanding the extraordinary effectiveness of mucin thin films as boundary lubricants.

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Liquid-crystalline order in mucus

Cited by 55 publications

References 1 publication

Mucin Granule Intraluminal Organization

Mucin Granule Intraluminal Organization

Unpacking a gel-forming mucin: a view of MUC5B organization after granular release

Structural hysteresis and hierarchy in adsorbed glycoproteins

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