BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 3. THE CELL AND EXTRACELLULAR MATRIX

3.3. Extracellular Matrix

According to modern concepts, the Extracellular matrix is a supramolecular complex that forms the cellular microenvironment and influences Cell Differentiation, proliferation, Organization, and attachment. It plays a pivotal role in Organogenesis, Embryogenesis, wound healing, tumor invasion, and metastasis. The matrix forms the rigid structures of bones and Teeth, constitutes the transparent substance of the cornea, and takes on a rope-like form that imparts high tensile strength to tendons. A specialized form of the extracellular matrix, the basement membrane, serves as a site for cell attachment and influences cell migration and phenotypic expression. The mechanical Stability of the basement membrane is ensured by type IV Collagen (Fig. 3.4; 5), which forms a meshwork rather than fibrils (unlike other collagen types - Fig. 3.4, 2). In addition to collagen, the basement membrane contains the glycoprotein Laminin (Fig. 3.4, 3), a cruciform Structure consisting of three polypeptide chains linked by Disulfide Bonds. This protein acts as an adhesive substrate for various Cells, enhances proliferation, and binds to Integrins, type IV collagen, and nidogen (entactin), a dumbbell-shaped molecule.

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Fig. 3.4. Main protein Components of the extracellular matrix:

1 - fibronectin; 2 - types I, II, III, V, VI and other collagens; 3 - laminin; 4 - proteoglycan; 5 - type IV collagen; 6 - Elastin; 7 — tenascin

The basement membrane consists of two layers: the electron-lucent layer (lamina lucida, or rara), which is adjacent to The Plasma Membrane of the cells "lying" on the basement membrane. Underlying this layer is the electron-dense layer (lamina densa). Occasionally, a third layer containing collagen fibrils (lamina reticularis) is also observed, which anchors the basement membrane to the Connective Tissue. The Functions of the basement membrane are diverse: as a molecular filter, it regulates the passage of molecules from Blood into urine; it serves as a selective barrier for cells (for instance, acting as a barrier between epithelial cells and connective tissue fibroblasts while allowing the passage of macrophages, lymphocytes, and nerve fibers); and it acts as a substrate for the migration of regenerating cells, coordinating the Spatial Organization of components on both sides of the synapse, among other functions.

An important component of the extracellular matrix is the collagen family (Fig. 3.4, 2, 5) - Fibrillar Proteins that account for 25% of all proteins in the mammalian body. The molecule appears as a 300 nm-long triple helix, which aggregates to form collagen fibrils (up to 300 nm in thick), which in turn bundle into collagen fibers several micrometers thick that are visible under a Light Microscope. This is the structural arrangement of types I, II, III, and other collagens, with the exception of type IV. Collagens contain "unconventional" Amino Acids - hydroxylysine and hydroxyproline (Fig. 3.5, 1, 2) - which form Hydrogen Bonds between Polypeptides and stabilize the triple helix.

Fig. 3.5. "Unconventional" amino acids of collagens:

1 - hydroxylysine; 2 — hydroxyproline

The hydroxylation of amino acids occurs within the cisternae of The Endoplasmic reticulum. Hydroxyproline is synthesized in the presence of ascorbic acid, or Vitamin C. In scurvy - a human disease caused by a deficiency of this vitamin - unhydroxylated chains fail to form a triple helix, Blood Vessels become fragile, and teeth begin to loosen. To date, over 20 different collagen chains have been identified, from which theoretically more than 1,000 types of triple-helical molecules can be assembled. In practice, only 10 collagens have been identified so far, among which types I, II, III, and IV are the most thoroughly studied. The first of these is the most abundant, making up 90% of the body's total collagen and found in almost all Organs (Table 3.2). These four collagens comprise Two Types of α-chains - α1 and α2.

Table 3.2

The four MAIN TYPES OF collagen and their properties

Certain Tissues must not only withstand mechanical stress but also be elastic. This is provided by elastin (Fig. 3.4, 6), a component of the extracellular matrix - a hydrophobic, non-glycosylated protein that contains little hydroxyproline and lacks hydroxylysine entirely. Through cross-links formed by Lysine residues, elastin forms a branched network capable of stretching up to 5 times more than a rubber band of equivalent cross-section. Collagen fibrils interwoven into this network (which are stronger than steel wire of the same diameter) limit its stretching and prevent tissue rupture.

The extracellular matrix also contains several adhesive Glycoproteins, namely the aforementioned laminin, as well as fibronectin and tenascin. Fibronectin (Fig. 3.4, 1) is a disulfide-linked dimer that exists in three forms. The soluble dimeric form (plasma fibronectin) promotes blood clotting, wound healing, and phagocytosis. Surface and matrix fibronectins are dimers assembled into oligomeric forms. Fibronectins are multifunctional molecules; they bind to cell receptors such as integrins, collagen, heparin, and other extracellular matrix components, thus participating in matrix assembly, cell attachment, intercellular adhesion, and the determination of cell migration pathways and morphogenetic movements.

Tenascin (Fig. 3.4, 7) is likewise an adhesive glycoprotein, though less widely distributed and most frequently found in embryonic tissues. The structure of tenascin resembles a wheel, with six disulfide-linked polypeptide chains acting as its spokes.

The second class of extracellular matrix macromolecules consists of Polysaccharides known as glycosaminoglycans - long, unbranched polysaccharide chains composed of repeating disaccharide units. These units typically consist of a hexose sulfated at the C-4 position (hence the name), such as N-acetylglucosamine or N-acetylgalactosamine, paired with a uronic acid (Fig. 3.6, 2). The presence of sulfate and carboxyl groups in their molecules imparts a significant negative charge to glycosaminoglycans, which attracts osmotically active Na⁺ ions. This leads to an increased Water content in the extracellular matrix, enabling it to resist compressive forces (in contrast to collagen fibers, which counteract tensile stress). Although glycosaminoglycans account for only 10% of extracellular matrix components, they occupy a greater volume because they form a loose, hydrated gel. Glycosaminoglycans are present in the extracellular matrices of all tissues and are divided into four groups: hyaluronic acid, chondroitin and dermatan sulfates, heparan sulfate and heparin, and keratan sulfate (Table 3.3).

Table 3.3

Glycosaminoglycans

In addition to D-glucuronic acid, dermatan sulfate often incorporates L-iduronic acid, which is formed by the epimerization of the former at the site of the carboxyl group attachment. This means that dermatan sulfate can be considered a modified form of chondroitin sulfate.

Hyaluronic acid consists of repeating unsulfated disaccharide units (Fig. 3.6, 2), is found in all animal tissues and fluids, and is particularly abundant in early embryos. This is because the acid performs a specialized function in areas undergoing cell migration and wound healing. Specifically, during morphogenesis and regeneration, local synthesis of hyaluronic acid increases, causing the matrix to swell. In synovial fluid, this acid acts as a lubricant. Hyaluronic acid is degraded by the enzyme hyaluronidase.

Fig. 3.6. Diagram showing the attachment of a glycosaminoglycan chain to a protein via a linking trisaccharide to form a proteoglycan:

1 - protein with a Serine residue; 2 — glycosaminoglycan

Glycosaminoglycans are widely distributed throughout the body. Hyaluronic acid is localized in various Connective Tissues, skin, vitreous body, cartilage, and synovial fluid. Chondroitin sulfate is found primarily in cartilage, cornea, bones, skin, and Arteries, whereas dermatan sulfate is located in the skin, blood vessels, Heart, and heart Valves. Heparan sulfate predominates in the Lungs, arteries, cell surfaces, and basement membrane. Heparin is present in the lungs, Liver, skin, and mast cells, while keratan sulfate is found in cartilage, cornea, and intervertebral discs.

With the exception of hyaluronic acid, all glycosaminoglycans are covalently bound to proteins in the form of Proteoglycans (Fig. 3.4, 4; 3.6). These proteins differ from glycoproteins in that they contain up to 95% CARBOHYDRATES (by mass) in the form of unbranched chains, each consisting of about 80 residues without sialic acids. Glycoproteins contain short (up to 15 sugar residues) branched oligosaccharide chains that frequently terminate with sialic acid.

Proteoglycans vary in their core protein, molecular weight, number, type, and length of glycosaminoglycan chains, as well as the distribution of hydroxyl, carboxyl, and sulfate groups, which provides them with almost limitless diversity. They bind via glycosaminoglycan chains to fibronectins, collagens, laminins, and growth factors, interact with The Cell surface, and some even serve as intrinsic integral components of the plasma membrane. Therefore, the question of where the plasma membrane ends and the extracellular matrix begins remains largely semantic.

Glycosaminoglycans and Proteoglycans within the matrix are linked to each other and to fibrillar proteins. For example, the principal cartilage proteoglycan, containing keratin and chondroitin sulfates, is organized within the matrix into large aggregates (Fig. 3.7) that are non-covalently bound via their core proteins to a hyaluronic acid macromolecule. Approximately 100 proteoglycan monomers bind to a single molecule of this acid, forming a giant complex with a Molecular Weight of 100 million (or more) that occupies a space equivalent to the volume of a bacterium.

Fig. 3.7. Cytology/cytology/92.html">SCHEMATIC STRUCTURE OF a giant proteoglycan aggregate:

1 - portion of the proteoglycan aggregate; 2 - hyaluronic acid core; 3 - keratan sulfate; 4 - chondroitin sulfate; 5 - link protein; 6 - core protein

Consequently, the extracellular matrix consists primarily of fibrillar proteins embedded in a hydrated polysaccharide gel. Due to the high density of negative charges of the latter, sodium ions are localized within the matrix, leading to strong Hydration of the gel. This generates turgor pressure (Swelling pressure). Meanwhile, proteins (mainly collagen, fibronectin, elastin, etc.) strengthen and organize the extracellular matrix, provide it with resilience, and facilitate cell attachment.

The basement membrane is a thin sheet of Specialized Extracellular Matrix. It underlies epithelial cell sheets, is located between two different cell layers in pulmonary alveoli and renal glomeruli, and envelops individual Muscle fibers and fat cells. These structures serve as structural support, a highly efficient filter, and a selective barrier; they determine cell polarity, influence cellular METABOLISM and differentiation, play a crucial role in tissue regeneration, coordinate the spatial organization of components on both sides of the synapse, occupy an important place in The regulation of morphogenesis, and organize carbohydrates and proteins in adjacent Plasma Membranes. In the latter case, this refers to the interaction between the extracellular matrix and the glycocalyx—the carbohydrate-rich extracellular surface of the plasma membrane. Through specialized receptor proteins, the Cytoskeleton, plasma membrane, and extracellular matrix are integrated into a dynamic, fluid structure. This ensures the transmission of mechanical signals across and along the membrane, plays a vital role in Cell Adhesion and immune responses, helps establish and maintain cell orientation within tissues and organs during development, and mediates the Transduction of external signals into biochemical processes.