Carbohydrates as Informational Molecules: The Sugar Code: - Lectin-Carbohydrate Interactions Are Very Strong and Highly Specific

In all the functions of lectins described above, and in many more known to involve lectin-oligosaccharide in teractions, it is essential that the oligosaccharide have a unique structure, so that recognition by the lectin is highly specific. The high density of information in oligosaccharides provides a sugar code with an essentially unlimited number of unique “words” small enough to be read by a single protein. In their carbohydrate binding sites, lectins have a subtle molecular complementarity that allows interaction only with their correct carbohydrate cognates. The result is extraordinarily high specificity in these interactions.

X-ray crystallographic studies of the structures of several lectin-carbohydrate complexes have provided rich details of the lectin-sugar interaction. Sialoadhesin (also called siglec-1) is a membrane-bound lectin on the surface of mouse macrophages that recognizes certain sialic acid–containing oligosaccharides. This protein has a β sandwich domain (see this motif in the CD8 protein in Fig. 4–22) that contains the sialic acid binding site (Fig. 7–35a). Each of the ring substituents unique to Neu5Ac is involved in the interaction between sugar and lectin; the acetyl group at C-5 undergoes both hydrogen bond and van der Waals interactions with the protein; the carboxyl group makes a salt bridge with Arg97; and the hydroxyls of the glycerol moiety hydrogen-bond with the protein (Fig. 7–35b).

The structure of the mannose 6-phosphate receptor/lectin has also been resolved crystallographic ally, revealing details of its interaction with mannose 6 phosphate that explain the specificity of the binding and the necessity for a divalent cation in the lectin-sugar interaction (Fig. 7–35c). Arg¹¹¹ of the receptor is hydrogen-bonded to the C-2 hydroxyl of mannose and coordinated with Mn²⁺. His¹⁰⁵ is hydrogen-bonded to one of the oxygen atoms of the phosphate (Fig. 7–35d). When the protein tagged with mannose 6-phosphate reaches the lysosome (which has a lower internal pH than the Golgi complex), the receptor apparently loses its affinity for mannose 6-phosphate. Protonation of His¹⁰⁵ may be responsible for this change in binding. In addition to these very specific interactions, there are more general interactions that contribute to the binding of many carbohydrates to their lectins. For ex ample, many sugars have a more polar and a less polar side (Fig. 7–36); the more polar side hydrogen-bonds with the lectin, while the less polar undergoes hydro phobic interactions with nonpolar amino acid residues. The sum of all these interactions produces high-affinity binding (K_d often 10^-8 M or less) and high specificity of lectins for their carbohydrates. This represents a kind of information transfer that is clearly central in many processes within and between cells. Figure 7–37 summarizes some of the biological interactions mediated by the sugar code.

FIGURE 7–35 Details of lectin-carbohydrate interaction. (a) X-ray crystallographic studies of a sialic acid–specific lectin (derived from PDB ID 1QFO) show how a protein can recognize and bind to a sialic acid (Neu5Ac) residue. Sialoadhesin (also called siglec-1), a membrane bound lectin of the surface of mouse macrophages, has a sandwich domain (gray) that contains the Neu5Ac binding site (dark blue). Neu5Ac is shown as a stick structure. (b) Each ring substituent unique to Neu5Ac is involved in the interaction between sugar and lectin: the acetyl group at C-5 has both hydrogen-bond and van der Waals inter actions with the protein; the carboxyl group makes a salt bridge with Arg⁹⁷; and the hydroxyls of the glycerol moiety hydrogen-bond with the protein. (c) Structure of the bovine mannose 6-phosphate receptor complexed with mannose 6-phosphate (PDB ID 1M6P). The protein is represented here as a surface contour image, with color to indicate the surface electrostatic potential: red, predominantly negative charge; blue, predominantly positive charge. Mannose 6-phosphate is shown as a stick structure; a manganese ion is shown in green. (d) In this complex, mannose 6-phosphate is hydrogen-bonded to Arg¹¹¹ and coordinated with the manganese ion (green). The His¹⁰⁵ hydrogen-bonded to a phosphate oxygen of mannose 6-phosphate may be the residue that, when protonated at low pH, causes the receptor to release mannose 6-phosphate into the lysosome.

FIGURE 7–36 Hydrophobic interactions of sugar residues. Sugar units such as galactose have a more polar side (the top of the chair, with the ring oxygen and several hydroxyls), available to hydrogen-bond with the lectin, and a less polar side that can have hydrophobic interactions with nonpolar side chains in the protein, such as the indole ring of tryptophan.

FIGURE 7–37 Roles of oligosaccharides in recognition and adhesion at the cell surface. (a) Oligosaccharides with unique structures (represented as strings of hexagons), components of a variety of glycoproteins or glycolipids on the outer surface of plasma membranes, interact with high specificity and affinity with lectins in the extracellular milieu. (b) Viruses that infect animal cells, such as the influenza virus, bind to cell surface glycoproteins as the first step in infection. (c) Bacterial toxins, such as the cholera and pertussis toxins, bind to a surface glycolipid before entering a cell. (d) Some bacteria, such as H. pylori, adhere to and then colonize or infect animal cells. (e) Selectins (lectins) in the plasma membrane of certain cells mediate cell-cell interactions, such as those of T lymphocytes with the endothelial cells of the capillary wall at an infection site. (f) The mannose 6-phosphate receptor/lectin of the trans Golgi complex binds to the oligosaccharide of lysosomal enzymes, targeting them for transfer into the lysosome.

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مواضيع ذات صلة

Nucleic Acid Structure:- DNA Stores Genetic Information

Carbohydrates as Informational Molecules: The Sugar Code:- Lectins Are Proteins That Read the Sugar Code and Mediate Many Biological Processes

Polysaccharides:- Glycolipids and Lipopolysaccharides Are Membrane Components

Polysaccharides: - Glycoproteins Have Covalently Attached Oligosaccharides

Polysaccharides:- Proteoglycans Are Glycosaminoglycan-Containing Macromolecules of the Cell Surface and Extracellular Matrix

Polysaccharides:- Glycosaminoglycans Are Heteropolysaccharides of the Extracellular Matrix

Polysaccharides:- Bacterial and Algal Cell Walls Contain Structural Hetero polysaccharides

Polysaccharides: -Steric Factors and Hydrogen Bonding Influence Homopolysaccharide Folding

Polysaccharides:- Some Homopolysaccharides Serve Structural Roles

Polysaccharides:- Some Homopolysaccharides Are Stored Forms of Fuel

Monosaccharides and Disaccharides:- Disaccharides Contain a Glycosidic Bond

Monosaccharides and Disaccharides:- Monosaccharides Are Reducing Agents