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Extracellular matrix assembly: a multiscale deconstruction

Key Points

  • Different tissues have unique and specialized extracellular matrix (ECM) components and organization, which enables each ECM to carry out tissue-specific roles, including structural support, the transmission of forces and macromolecular filtration. The architecture of the ECM is highly organized, which partly arises from the innate properties of its constituent molecules and their interactions and partly from the activities of the resident cells.

  • The fibrous (collagens and elastin) and glycoprotein (fibronectin, proteoglycans and laminins) macromolecules that constitute the ECM have evolved structures and chemical properties that are particularly suited to their specific biological functions in their respective tissues. Each class of ECM molecule is designed to interact with another class to produce unique physical and signalling properties that support tissue structure, growth and function. Small, modular subunits form homopolymers and heteropolymers that become supramolecular assemblies with highly specialized organization.

  • Collagens are the major proteins of the ECM. The structural hallmark of all collagens is the triple helix, which is a right-handed helix of three polypeptide α-chains (homotrimers and heterotrimers), each of which contains one or more regions that are characterized by the repeating amino acid motif Gly-X-Y, where X and Y can be any amino acid.

  • The assembly of fibrillar collagen involves multiple complex intracellular and extracellular post-translational steps from the translational product to a fibrillar structure that is capable of withstanding tensile forces. The unique mechanical properties of fibrillar collagen are mainly controlled by the collagen structure, which shows the importance of the relationship between three-dimensional protein structure and the resulting ECM function.

  • The primary biological function of proteoglycans derives from the biochemical and hydrodynamic characteristics of the glycosaminoglycan (GAG) components of the molecules, which are long, negatively charged, linear chains of disaccharide repeats that bind water to provide hydration and compressive resistance. Heparan sulphate proteoglycans (HSPGs) are a major part of the basement membrane and chondroitin sulphate proteoglycans (CSPGs) can be found in cartilage and in neural ECMs.

  • The laminin family of large, mosaic glycoproteins are primarily located in basal lamina and some mesenchymal compartments, and they mediate interactions between cells via cell surface receptors (such as integrins and dystroglycan) and other components of the ECM through the modular domains within the laminin molecule. Similarly, many ECM proteins interact with cells through crucial connections with the multidomain protein fibronectin, which is secreted as a large glycoprotein that assembles via cell-mediated processes into fibrillar structures around cells.

  • The production and assembly of the ECM follow different temporal and spatial patterns in various tissues, with load-bearing tissues such as tendons showing highly ordered, fibrillar structures and the continually evolving brain showing a less organized, GAG-rich ECM. Therefore, disruption of the relative abundance of ECM proteins or their interactions with one another has important consequences for the behaviour and the fate of cells within that tissue.

Abstract

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.

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Figure 1: Collagen structure.
Figure 2: Fibrillar collagen assembly.
Figure 3: Non-collagenous molecules of the ECM.
Figure 4: Basal lamina assembly.
Figure 5: Perineuronal nets.

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Acknowledgements

The authors apologize to all colleagues whose work cannot be cited owing to space limitations. This work was supported by DOD Breast Cancer Research Program (BCRP) grant W81XWH-07-1-0538 (to J.K.M.), US National Science Foundation (NSF) Graduate Research Fellowship (to G.O.), DOD BCRP grants W81XWH-05-1-0330 and W81XWH-13-1-0216 (to V.M.W.), US National Institutes of Health National Cancer Institute (NCI) grants R01 CA138818, U54 CA143836, R01 CA085492 and U01 ES019458 (to V.M.W.), and Susan G. Komen grant KG110560PP (to V.M.W.).

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PowerPoint slides

Glossary

Topographies

The three-dimensional qualities of surfaces or structures, including contours and relief. In the context of the ECM this includes features such as peaks and valleys, changes in roughness and geometric features.

Morphogenesis

The process of cell movement during embryonic development that controls the size, the shape and the patterning of tissues and organs.

Proteoglycans

(PGs). Glycoproteins that consist of a core protein to which one or more glycosaminoglycan chain is attached.

Glycosaminoglycans

(GAGs). Long, linear, charged polysaccharides that comprise repeating pairs of sugars, of which one is an amino sugar.

Fibrillar collagen

Polymerized, supramolecular collagen that has been organized into fibrils; collagen types I, II and III form fibrils.

Tensile forces

The forces required to exert a certain amount of tension (which is a type of normal stress) on a one-dimensional object. In this context, a pulling force on a cable tending to cause extension of the cable.

Procollagen

A trimeric collagen precursor molecule containing large amino- and carboxy-terminal propeptide domains.

Lysyl oxidase

An enzyme that participates in the formation of collagen polymers by facilitating oxidative deamination of peptidyl lysine residues on collagen monomers.

Pericellular space

The space surrounding a cell.

Fibripositors

(Also known as fibropositors). Plasma membrane protrusions projecting from the cell surface, where procollagen can potentially be processed, assembled and organized by individual cells.

Fibrillogenesis

The development or formation of fibrils, used to refer to collagen- or fibronectin-rich structures.

Small leucine-rich repeat proteoglycans

(SLRPs). A family of proteoglycans that share a common leucine-rich-repeat motif in their conserved carboxy termini; they have been strongly implicated in modulating fibrillar collagen assembly.

FACIT

(Fibril-associated collagens with interrupted triple helices). A type of collagen that does not form fibrils by itself but that is associated with the surface of fibrillar collagen.

Basement membrane

A thin, complex extracellular matrix that separates endothelial and epithelial cells from their subjacent connective tissues. It is composed of various collagens, proteoglycans and adhesive glycoproteins.

Syndecans

One of the two major families of heparin sulphate proteoglycans.

Glypicans

One of the two major families of heparin sulphate proteoglycans.

Epimerization

The formation of stereoisomers.

Integrins

A large family of heterodimeric transmembrane proteins, which are present in the plasma membrane as heterodimers of α- and β-subunits and function as receptors for cell adhesion molecules.

Nidogens

(Also known as entactins). Glycoproteins and key parts of the basement membrane.

Fibrillar adhesions

Cell–matrix connections that are typified by their location near the centre of the cell and their higher length to width ratio compared with focal adhesions at the periphery of cells.

Fascicles

Bundles of fibres.

Reticular lamina

A collagen-rich layer that is often found below the basal lamina that connects the combined basement membrane to the connective tissue.

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Mouw, J., Ou, G. & Weaver, V. Extracellular matrix assembly: a multiscale deconstruction. Nat Rev Mol Cell Biol 15, 771–785 (2014). https://doi.org/10.1038/nrm3902

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