BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

CHAPTER 15. BIOCHEMISTRY OF THE EXTRACELLULAR MATRIX

IV. Specialized Proteins of the Extracellular Matrix

Extracellular matrix Proteins perform diverse functions, but they can be divided into two major groups based on one very important feature: 1) proteins with adhesive properties; and 2) proteins that inhibit Cell Adhesion.

A. Adhesive Proteins

The first group comprises proteins with pronounced adhesive properties, including Fibronectin, Laminin, nidogen, fibrillar collagens, and type IV Collagen; these are typically found in "mature" Connective Tissue.

Fibronectin

Fibronectin is one of the key Proteins of the extracellular matrix, a non-collagenous structural glycoprotein synthesized and secreted into the intercellular space by many cell types. It is composed of two identical polypeptide chains linked by Disulfide Bonds near their C-termini (Fig. 15-19).

Class="center">Fig. 15-19. Structure of fibronectin.

The polypeptide chain of fibronectin contains 7-8 domains, each featuring specific binding sites for various molecules. Fibronectin can bind collagen, Proteoglycans, hyaluronic acid, plasma Membrane CARBOHYDRATES, heparin, and the enzyme transglutaminase. Due to its unique structure, fibronectin plays an integrative role in the Organization OF THE extracellular substance and promotes cell adhesion.

There are several forms of fibronectin synthesized by different cell types. Soluble, or plasma, fibronectin is synthesized by hepatocytes. Insoluble, or cellular, fibronectin is produced primarily by fibroblasts, endothelial Cells, glial cells, and epithelial cells.

Both forms of fibronectin are involved in a wide range of processes: they promote the adhesion and spreading of epithelial and mesenchymal cells, stimulate the proliferation and migration of embryonic and tumor cells, control Cell Differentiation and the Maintenance of the Cytoskeleton, and actively participate in inflammatory and reparative processes. This is because each fibronectin subunit contains the Arg-Gly-Asp (RGD) sequence, which allows it to attach to cellular receptors (Integrins). These receptors interact indirectly with cytosolic Actin microfilaments. This process involves so-called attachment proteins (such as talin, vinculin, and α-actinin) (Fig. 15-20).

Through such Protein-Protein Interactions, information can be transmitted from the extracellular matrix into The Cell, as well as in the reverse direction from the cell outward, thereby influencing intracellular processes.

Fig. 15-20. Diagram of fibronectin interaction with integrin.

Fibronectin is also known to participate in the migration of cells that attach to its RGD domains, essentially serving as a guide that helps them move through the extracellular matrix.

In the extracellular matrix surrounding transformed (or tumor) cells, The amount of fibronectin is markedly reduced, which may be one of the factors contributing to metastasis.

Laminin is the most abundant non-collagenous glycoprotein of basement membranes. It consists of three polypeptide chains: A, B₁, and B₂. The laminin molecule has a cross-like shape with three single-chain arms and one three-chain arm (Fig. 15-21). Each laminin chain contains several globular and rod-like domains with specific binding sites for various substances. Laminin interacts with all Structural components of basement membranes, including type IV collagen, nidogen, fibronectin, and heparan sulfate proteoglycans (HSPG). In addition, the laminin molecule possesses multiple cell-binding sites. The primary functions of laminin are determined by its ability to bind cells and modulate cellular behavior, influencing cell growth, Morphology, differentiation, and motility.

Fig. 15-21. STRUCTURE OF THE laminin-nidogen complex.

Laminin acts as an adhesive protein for various epithelial and mesenchymal cells.

Nidogen (entactin) is a sulfated basement membrane glycoprotein that forms a tight, non-covalently bound complex with laminin; the binding affinity of nidogen for type IV collagen is much lower than for laminin. This protein consists of a single polypeptide chain containing three globular domains (Fig. 15-21). One of the nidogen domains contains the laminin-binding site, while another houses the type IV collagen-binding site. Thus, nidogen can act as a connecting bridge between various extracellular matrix components, participating in The formation of ternary laminin-nidogen-collagen complexes. Furthermore, nidogen contains an RGD sequence and is therefore capable of attaching to the cell surface.

B. Anti-Adhesive Proteins

The second group of proteins with anti-adhesive properties includes such Glycoproteins as osteonectin, tenascin, and thrombospondin. These proteins emerge and play prominent roles during Embryogenesis and morphogenesis, as well as in the cellular response to injury. Their concentration in the matrix increases in certain tumor pathologies.

Osteonectin (synonyms: BM-40, SPARC; secreted protein acidic and rich in Cysteine) consists of 4 domains, 2 of which can bind Ca²⁺ ions. Osteonectin is an acidic, cysteine-rich protein. It has been shown to inhibit the G₁-S phase of endothelial cell proliferation.

Tenascin (myotendinous antigen) is an oligomeric glycoprotein composed of two disulfide-linked subunits, much like fibronectin. This large, octopus-like molecule is also known as a hexabrachion because it features six arms radiating from a central hub. Due to this unique architecture, tenascin can interact with a wide range of ligands, including various extracellular matrix molecules.

Tenascin exhibits both adhesive and anti-adhesive properties and is synthesized in various embryonic tissues, most prominently at epithelial-mesenchymal interfaces and within the developing Nervous Tissue. In mature tissues, trace amounts of tenascin are found in tendons and Cartilage, while its synthesis significantly increases during wound healing.

Thrombospondin, like other extracellular matrix proteins, is capable of interacting with numerous ligands, including collagen, fibronectin, laminin, proteoglycans, Ca²⁺ ions, and others. In corneal cells and platelets, thrombospondin displays adhesive properties, whereas in endothelial cells and fibroblasts, it functions as an anti-adhesive protein.

Thus, the functions of these proteins are determined by their specific localization and microenvironment.