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

SECTION 5. BIOLOGICAL MEMBRANES

IV. The Role of Membranes in Intercellular Interactions

Cell/30.html">The Plasma Membrane of Eukaryotic Cells contains numerous specialized receptors that interact with ligands to trigger specific cellular responses. Some receptors bind signaling molecules such as Hormones and Neurotransmitters, others bind nutrients and metabolites, and still others are involved in Cell Adhesion. This Class includes receptors essential for mutual Cell Recognition and adhesion, as well as those responsible for binding cells to Extracellular matrix Proteins like Fibronectin or Collagen.

The ability of cells to undergo specific mutual recognition and adhesion is vital for embryonic development. In adults, cell-cell and cell-matrix adhesive interactions remain critical for maintaining tissue integrity. Among the large family of cell adhesion receptors, Integrins, selectins, and cadherins are the most extensively studied.

Integrins — a vast superfamily of homologous cell-surface receptors for extracellular matrix molecules, such as collagen, fibronectin, Laminin, and others. As transmembrane proteins, they interact with both extracellular molecules and intracellular cytoskeletal proteins. Consequently, integrins play a key role in signal Transduction from the extracellular environment into The Cell, thereby determining its differentiation pathway, shape, mitotic activity, and migratory capacity. Signaling can also proceed in the reverse direction—from intracellular proteins through the receptor to the extracellular matrix.

Approximately 20 different members of this receptor family have been identified across various cell types.

Examples of certain integrins include:

✵ Receptors for extracellular matrix proteins. They bind to glycoprotein Components of the extracellular matrix, notably fibronectin, laminin, and vitronectin (see Section 15);

✵ Platelet integrins (IIb and IIIa), which are involved in platelet aggregation during Blood clotting;

✵ Leukocyte adhesion proteins. To migrate to sites of infection and inflammation, leukocytes must interact with vascular endothelial cells. This interaction can mediate the binding of T lymphocytes to fibroblasts during inflammation.

Integrins are heterodimers, with each subunit (α, β) containing a single transmembrane domain (Fig. 5-26).

Fig. 5-26. Fibronectin receptor. The fibronectin receptor belongs to the integrin family. Each subunit has a single transmembrane domain, a short cytoplasmic domain, and an extended extracellular N-terminal domain. Both integrin subunits (α, β) are glycosylated and held together by noncovalent bonds. The α-subunit is synthesized as a single polypeptide chain, which is subsequently cleaved into a small transmembrane chain and a large extracellular chain linked by disulfide bridges. The β-subunit contains four repeats of 40 amino acid residues each. The α-subunits are rich in Cysteine and contain multiple intrachain Disulfide Bonds (not shown in the figure). By binding to fibronectin on the outside and to the Cytoskeleton on the inside of the cell, the integrin acts as a transmembrane linker.

Individual integrins are strictly specific. The integrin binding site is formed by the extracellular domains of the α- and β-subunits. Integrins recognize and bind to proteins containing a specific Amino Acid Sequence, -Arg-Gly-Asp-, present in A number of matrix proteins (fibronectin, fibrinogen, laminin, type I collagen, and others). The binding effect is enhanced in the presence of Ca²⁺ and Mg²⁺ ions.

Cadherins and selectins — families of transmembrane Ca²⁺-dependent Glycoproteins involved in cell-cell adhesion. Three possible modes of participation of these receptor types in cell-cell adhesion are shown in Fig. 5-27.

Fig. 5-27. Modes of interaction between cell surface molecules during cell-cell adhesion. A — receptors on one cell can bind to identical receptors on neighboring cells (homophilic binding); B — receptors on one cell can bind to a different type of receptor on neighboring cells (heterophilic binding); C — cell surface receptors of neighboring cells can bind to each other via multivalent linker molecules.

Cadherins from different Tissues are very similar, with homologous Amino acid sequences sharing 50 — 60% identity. Each receptor contains a single transmembrane domain. In the absence of Ca²⁺, the conformation of cadherins alters, making them susceptible to Proteolytic Enzymes that degrade them. The 3 main groups of cadherin receptors have been most thoroughly characterized:

✵ E-cadherin is found On the surface of various epithelial and embryonic cells;

✵ N-cadherin is localized on The surface of Nerve Cells, cardiac cells, and lens cells;

✵ P-cadherin is located on placental and epidermal cells.

Cadherins play a crucial role in initial intercellular adhesion during the stages of morphogenesis and Organogenesis. They ensure the structural integrity and polarity of tissues, particularly the epithelial monolayer.

Within the selectin receptor family, three proteins are the most thoroughly studied: L-selectin, P-selectin, and E-selectin. The extracellular region of selectins consists of 3 domains: the first domain contains 2–9 repeating amino acid blocks (Complement-regulatory protein), the second is an epidermal growth factor (EGF)-like domain, and the third is an N-terminal lectin domain (Fig. 5-28). L-, P-, and E-selectins differ in the number of blocks within their complement-regulatory protein domain. Lectins are a family of proteins that specifically interact with particular carbohydrate residue sequences found in glycoproteins, Proteoglycans, and Glycolipids of the extracellular matrix.

Fig. 5-28. Structure of selectins.

Carbohydrate structures are polyvalent linker molecules that can be sulfated, fucosylated, and sialylated—meaning they may contain sulfuric acid, fucose, and sialic acid residues. Ligand binding to receptors occurs within the N-terminal lectin domain.