Key Concepts Of Section

Sheetlike Epithelial Tissues: Junctions and Adhesion Molecules

■ Polarized epithelial cells have distinct apical, basal, and lateral surfaces. Microvilli projecting from the apical surfaces of many epithelial cells considerably expand their surface areas.

■ Three major classes of cell junctions—anchoring junctions, tight junctions, and gap junctions—assemble epithelial cells into sheets and mediate communication between them (see Figures 6-1 and 6-5).

■ Adherens junctions and desmosomes are cadherin-containing anchoring junctions that bind the membranes of adjacent cells, giving strength and rigidity to the entire tissue. Hemidesmosomes are integrin-containing anchoring junctions that attach cells to elements of the underlying extracellular matrix.

■ Cadherins are cell-adhesion molecules (CAMs) responsible for Ca2+-dependent interactions between cells in epithelial and other tissues. They promote strong cell-cell adhesion by mediating both lateral and intercellular interactions.

■ Adapter proteins that bind to the cytosolic domain of cadherins and other CAMs mediate the association of cytoskeletal and signaling molecules with the plasma membrane (see Figure 6-9). Strong cell-cell adhesion depends on the linkage of the interacting CAMs to the cytoskeleton.

■ Tight junctions block the diffusion of proteins and some lipids in the plane of the plasma membrane, contributing to the polarity of epithelial cells. They also limit and regulate the extracellular (paracellular) flow of water and solutes from one side of the epithelium to the other (see Figure 6-11).

■ Integrins are a large family of ap heterodimeric cell-surface proteins that mediate both cell-cell and cellmatrix adhesions and inside-out and outside-in signaling in numerous tissues.

6.3| The Extracellular Matrix of Epithelial Sheets

In animals, the extracellular matrix helps organize cells into tissues and coordinates their cellular functions by activating intracellular signaling pathways that control cell growth, proliferation, and gene expression. Many functions of the matrix require transmembrane adhesion receptors that bind directly to ECM components and that also interact, through adapter proteins, with the cy-toskeleton. The principal class of adhesion receptors that mediate cell-matrix adhesion are integrins, which were introduced in Section 6.2. However, other types of molecules also function as important adhesion receptors in some nonepithelial tissues.

Three types of molecules are abundant in the extracellular matrix of all tissues.

■ Highly viscous proteoglycans, a group of glycoproteins that cushion cells and bind a wide variety of extracellular molecules

■ Collagen fibers, which provide mechanical strength and resilience

■ Soluble multiadhesive matrix proteins, which bind to and cross-link cell-surface adhesion receptors and other ECM components

We begin our description of the structures and functions of these major ECM components in this section, focusing on the molecular components and organization of the basal lamina—the specialized extracellular matrix that helps determine the overall architecture of an epithelial tissue. In Section 6.4, we extend our discussion to specific ECM molecules that are commonly present in nonepithelial tissues.

▲ EXPERIMENTAL FIGURE 6-12 The basal lamina separates epithelial cells and some other cells from connective tissue. (a) Transmission electron micrograph of a thin section of cells (top) and underlying connective tissue (bottom). The electron-dense layer of the basal lamina can be seen to follow the undulation of the basal surface of the cells. (b) Electron micrograph of a quick-freeze deep-etch preparation of

The Basal Lamina Provides a Foundation for Epithelial Sheets

In animals, epithelia and most organized groups of cells are underlain or surrounded by the basal lamina, a sheetlike meshwork of ECM components usually no more than 60-120 nm thick (Figure 6-12; see also Figures 6-1 and skeletal muscle showing the relation of the plasma membrane, basal lamina, and surrounding connective tissue. In this preparation, the basal lamina is revealed as a meshwork of filamentous proteins that associate with the plasma membrane and the thicker collagen fibers of the connective tissue. [Part (a) courtesy of P FitzGerald. Part (b) from D. W. Fawcett, 1981, The Cell, 2d ed., Saunders/Photo Researchers; courtesy of John Heuser.]

6-4). The basal lamina is structured differently in different tissues. In columnar and other epithelia (e.g., intestinal lining, skin), it is a foundation on which only one surface of the cells rests. In other tissues, such as muscle or fat, the basal lamina surrounds each cell. Basal laminae play important roles in regeneration after tissue damage and in embryonic development. For instance, the basal lamina helps

Type IV collagen

Entactin

4 FIGURE 6-13 Major components of the basal lamina. Schematic model of basal lamina showing the organization of the major protein components. Type IV collagen and laminin each form two-dimensional networks, which are cross-linked by entactin and perlecan molecules. [Adapted from B. Alberts et al., 1994, Molecular Biology of the Cell, 3d ed., Garland, p. 991.]

Type IV collagen

Entactin

Perlecan

Perlecan

four- and eight-celled embryos adhere together in a ball. In the development of the nervous system, neurons migrate along ECM pathways that contain basal lamina components. Thus the basal lamina is important not only for organizing cells into tissues but also for tissue repair and for guiding migrating cells during tissue formation.

Most of the ECM components in the basal lamina are synthesized by the cells that rest on it. Four ubiquitous protein components are found in basal laminae (Figure 6-13):

■ Type IV collagen, trimeric molecules with both rodlike and globular domains that form a two-dimensional network

■ Laminins, a family of multiadhesive proteins that form a fibrous two-dimensional network with type IV collagen and that also bind to integrins

■ Entactin (also called nidogen), a rodlike molecule that cross-links type IV collagen and laminin and helps incorporate other components into the ECM

■ Perlecan, a large multidomain proteoglycan that binds to and cross-links many ECM components and cell-surface molecules

As depicted in Figure 6-1, one side of the basal lamina is linked to cells by adhesion receptors, including a6^4 integrin that binds to laminin in the basal lamina. The other side of the basal lamina is anchored to the adjacent connective tissue by a layer of fibers of collagen embedded in a proteoglycan-rich matrix. In stratified squamous epithelia (e.g., skin), this linkage is mediated by anchoring fibrils of type VII collagen. Together, the basal lamina and this collagen-containing layer (see the micrograph on page 197) form the structure called the basement membrane.

Sheet-Forming Type IV Collagen Is a Major Structural Component in Basal Laminae

Type IV collagen, the principal component of all basal lamina, is one of more than 20 types of collagen that participate in the formation of the extracellular matrix in various tissues. Although they differ in certain structural features and tissue distribution, all collagens are trimeric proteins made from three polypeptides called collagen a chains. All three a chains can be identical (homotrimeric) or different (het-erotrimeric). A trimeric collagen molecule contains one or more three-stranded segments, each with a similar triple-helical structure (Figure 6-14a). Each strand contributed by one of the a chains is twisted into a left-handed helix, and three such strands from the three a chains wrap around each other to form a right-handed triple helix.

The collagen triple helix can form because of an unusual abundance of three amino acids: glycine, proline, and a modified form of proline called hydroxyproline (see Figure 3-12). They make up the characteristic repeating motif Gly-X-Y, where X and Y can be any amino

▲ FIGURE 6-14 The collagen triple helix. (a) (Left) Side view of the crystal structure of a polypeptide fragment whose sequence is based on repeating sets of three amino acids, Gly-X-Y, characteristic of collagen a chains. (Center) Each chain is twisted into a left-handed helix, and three chains wrap around each other to form a right-handed triple helix. The schematic model (right) clearly illustrates the triple helical nature of the structure. (b) View down the axis of the triple helix. The proton side chains of the glycine residues (orange) point into the very narrow space between the polypeptide chains in the center of the triple helix. In mutations in collagen in which other amino acids replace glycine, the proton in glycine is replaced by larger groups that disrupt the packing of the chains and destablize the triple-helical structure. [Adapted from R. Z. Kramer et al., 2001, J. Mol. Biol. 311(1):131.]

acid but are often proline and hydroxyproline and less often lysine and hydroxylysine. Glycine is essential because its small side chain, a hydrogen atom, is the only one that can fit into the crowded center of the three-stranded helix (Figure 6-14b). Hydrogen bonds help hold the three chains together. Although the rigid peptidyl-proline and peptidyl-hydroxyproline linkages are not compatible with formation of a classic single-stranded a helix, they stabilize the distinctive three-stranded collagen helix. The hydroxyl group in hydroxyproline helps hold its ring in a conformation that stabilizes the three-stranded helix.

The unique properties of each type of collagen are due mainly to differences in (1) the number and lengths of the collagenous, triple-helical segments; (2) the segments that flank or interrupt the triple-helical segments and that fold into other kinds of three-dimensional structures; and (3) the covalent modification of the a chains (e.g., hydroxylation, glycosylation, oxidation, cross-linking). For example, the chains in type IV collagen, which is unique to basal laminae, are designated IVa chains. Mammals express six homologous IVa chains, which assemble into a series of type IV

Nonhelical Triple helical

Nonhelical Triple helical

Association
(b) Type IV network
250 nm

▲ FIGURE 6-15 Structure and assembly of type IV collagen.

(a) Schematic representation of type IV collagen. This 400-nm-long molecule has a small noncollagenous globular domain at the N-terminus and a large globular domain at the C-terminus. The triple helix is interrupted by nonhelical segments that introduce flexible kinks in the molecule. Lateral interactions between triple helical segments, as well as head-to-head and tail-to-tail interactions between the globular domains, form dimers, tetramers, and higher-order complexes, yielding a sheetlike network. (b) Electron micrograph of type IV collagen network formed in vitro. The lacy appearance results from the flexibility of the molecule, the side-to-side binding between triple-helical segments (thin arrows), and the interactions between C-terminal globular domains (thick arrows). [Part (a) adapted from A. Boutaud, 2000, J. Biol. Chem. 275:30716. Part (b) courtesy of P Yurchenco; see P Yurchenco and G. C. Ruben, 1987, J. Cell Biol. 105:2559.]

collagens with distinct properties. All subtypes of type IV collagen, however, form a 400-nm-long triple helix that is interrupted about 24 times with nonhelical segments and flanked by large globular domains at the C-termini of the chains and smaller globular domains at the N-termini. The nonhelical regions introduce flexibility into the molecule. Through both lateral associations and interactions entailing the globular N- and C-termini, type IV collagen molecules assemble into a branching, irregular two-dimensional fibrous network that forms the lattice on which the basal lamina is built (Figure 6-15).

HIn the kidney, a double basal lamina, the glomerular basement membrane, separates the epithelium that lines the urinary space from the endothelium that lines the surrounding blood-filled capillaries. Defects in this structure, which is responsible for ultrafiltration of the blood and initial urine formation, can lead to renal failure. For instance, mutations that alter the C-terminal globular domain of certain IVa chains are associated with progressive renal failure as well as sensorineural hearing loss and ocular abnormalities, a condition known as Alport's syndrome. In Goodpasture's syndrome, a relatively rare autoimmune disease, self-attacking, or "auto," antibodies bind to the a3 chains of type IV collagen found in the glomerular basement membrane and lungs. This binding sets off an immune response that causes cellular damage resulting in progressive renal failure and pulmonary hemorrhage.I

Laminin, a Multiadhesive Matrix Protein, Helps Cross-link Components of the Basal Lamina

Multiadhesive matrix proteins are long, flexible molecules that contain multiple domains responsible for binding various types of collagen, other matrix proteins, polysaccharides, cell-surface adhesion receptors, and extracellular signaling molecules (e.g., growth factors and hormones). These proteins are important for organizing the other components of the extracellular matrix and for regulating cell-matrix adhesion, cell migration, and cell shape in both epithelial and nonepithelial tissues.

Laminin, the principal multiadhesive matrix protein in basal laminae, is a heterotrimeric, cross-shaped protein with a total molecular weight of 820,000 (Figure 6-16). Many laminin isoforms, containing slightly different polypeptide chains, have been identified. Globular LG domains at the C-terminus of the laminin a subunit mediate Ca2 +-dependent binding to specific carbohydrates on certain cell-surface molecules such as syndecan and dystroglycan. LG domains are found in a wide variety of proteins and can mediate binding to steroids and proteins as well as carbohydrates. For example, LG domains in the a chain of laminin can mediate binding to certain integrins, including a6p4 integrin on epithelial cells.

▲ FIGURE 6-16 Laminin, a heterotrimeric multiadhesive matrix protein found in all basal laminae. (a) Schematic model showing the general shape, location of globular domains, and coiled-coil region in which laminin's three chains are covalently linked by several disulfide bonds. Different regions of laminin bind to cell-surface receptors and various matrix components. (b) Electron micrographs of intact laminin molecule, showing its characteristic cross appearance (left) and the carbohydrate-binding LG domains near the C-terminus (right). [Part (a) adapted from G. R. Martin and R. Timpl, 1987, Ann. Rev. Cell Biol. 3:57, and K. Yamada, 1991, J. Biol. Chem. 266:12809. Part (b) from R. Timpl et al., 2000, Matrix Biol. 19:309; photograph at right courtesy of Jürgen Engel.]

Secreted and Cell-Surface Proteoglycans Are Expressed by Many Cell Types

Proteoglycans are a subset of glycoproteins containing covalently linked specialized polysaccharide chains called glycosaminoglycans (GAGs), which are long linear polymers of specific repeating disaccharides. Usually one sugar is either a uronic acid (d-glucuronic acid or l-iduronic acid) or d-galactose; the other sugar is A-acetylglucosamine or ^-acetylgalactosamine (Figure 6-17). One or both of the sugars contain at least one anionic group (carboxylate or sulfate). Thus each GAG chain bears many negative charges.

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