The diversity and complexity of the carbohydrate units and the variety of ways in which they can be joined in oligosaccharides and polysaccharides suggest that they are functionally important. Nature does not construct complex patterns when simple ones suffice. Why all this intricacy and diversity? It is now clear that these carbohydrate structures are the recognition sites for a special class of proteins. Such proteins, termed glycan-binding proteins, bind specific carbohydrate structures on neighboring cell surfaces. Originally discovered in plants, glycan-binding proteins are ubiquitous, and no living organisms have been found that lack these key proteins. We will focus on a particular class of glycan-binding proteins termed lectins (from Latin legere, “to select”). The interaction of lectins with their carbohydrate partners is another example of carbohydrates being information-rich molecules that guide many biological processes. The diverse carbohydrate structures displayed on cell surfaces are well-suited to serving as sites of interaction between cells and their environments. Interestingly, the partners for lectin binding are often the carbohydrate moiety of glycoproteins.

334

Cell–cell contact is a vital interaction in a host of biochemical functions, ranging from building a tissue from isolated cells to facilitating the transmission of information. The chief function of lectins is to facilitate cell–cell contact. A lectin usually contains two or more carbohydrate-binding sites. The lectins on the surface of one cell interact with arrays of carbohydrates displayed on the surface of another cell. Lectins and carbohydrates are linked by a number of weak noncovalent interactions that ensure specificity yet permit unlinking as needed. The weak interactions between one cell surface and another resemble the action of Velcro; each interaction is weak, but the composite is strong.

We have already met a lectin obliquely. Recall that, in I-cell disease, lysosomal enzymes lack the appropriate mannose 6-phosphate, a molecule that directs the enzymes to the lysosome. Under normal circumstances, the mannose 6-phosphate receptor, a lectin, binds the enzymes in the Golgi apparatus and directs them to the lysosome.

Lectins can be divided into classes on the basis of their amino acid sequences and biochemical properties. One large class is the C type (for calcium-requiring) found in animals. These proteins each have a homologous domain of 120 amino acids that is responsible for carbohydrate binding. The structure of one such domain bound to a carbohydrate target is shown in Figure 11.30.

A calcium ion on the protein acts as a bridge between the protein and the sugar through direct interactions with sugar OH groups. In addition, two glutamate residues in the protein bind to both the calcium ion and the sugar, and other protein side chains form hydrogen bonds with other OH groups on the carbohydrate. The carbohydrate-binding specificity of a particular lectin is determined by the amino acid residues that bind the carbohydrate. C-type lectins function in a variety of cellular activities, including receptor-mediated endocytosis, a process by which soluble molecules are bound to the cell surface and subsequently internalized (Section 26.3), and cell–cell recognition.

335

Proteins termed selectins are members of the C-type family. Selectins bind immune-system cells to sites of injury in the inflammatory response. The L, E, and P forms of selectins bind specifically to carbohydrates on lymph-node vessels, endothelium, or activated blood platelets, respectively. New therapeutic agents that control inflammation may emerge from a deeper understanding of how selectins bind and distinguish different carbohydrates. L-Selectin, originally thought to participate only in the immune response, is produced by embryos when they are ready to attach to the endometrium of the mother’s uterus. For a short period of time, the endometrial cells present an oligosaccharide on the cell surface. When the embryo attaches through lectins, the attachment activates signal pathways in the endometrium to make implantation of the embryo possible.

Another large class of lectins comprises the L-lectins. These lectins are especially rich in the seeds of leguminous plants, and many of the initial biochemical characterizations of lectins were performed on this readily available lectin. Although the exact role of lectins in plants is unclear, they can serve as potent insecticides. Other L-type lectins, such as calnexin and calreticulin, are prominent chaperones in the eukaryotic endoplasmic reticulum. Recall that chaperones are proteins that facilitate the folding of other proteins.

Many pathogens gain entry into specific host cells by adhering to cell-surface carbohydrates. For example, influenza virus recognizes sialic acid residues linked to galactose residues that are present on cell- surface glycoproteins. The viral protein that binds to these sugars is called hemagglutinin (Figure 11.31A).

After binding hemagglutinin, the virus is engulfed by the cell and begins to replicate. To exit the cell, a process essentially the reverse of viral entry occurs (Figure 11.31B). Viral assembly results in the budding of the viral particle from the cell. Upon complete assembly, the viral particle is still attached to sialic acid residues of the cell membrane by hemagglutinin on the surface of the new virions. Another viral protein, neuraminidase (sialidase), cleaves the glycosidic bonds between the sialic acid residues and the rest of the cellular glycoprotein, freeing the virus to infect new cells, and thus spreading the infection throughout the respiratory tract. Inhibitors of this enzyme such as oseltamivir (Tamiflu) and zanamivir (Relenza) are important anti-influenza agents.

336

Viral hemagglutinin’s carbohydrate-binding specificity may play an important role in species specificity of infection and ease of transmission. For instance, avian influenza H5N1 (bird flu) is especially lethal and is readily spread from bird to bird. Although human beings can be infected by this virus, infection is rare and human-to-human transmission is rarer still. The biochemical basis of these characteristics is that the avian-virus hemagglutinin recognizes a different carbohydrate sequence from that recognized in human influenza. Although human beings have the sequence to which the avian virus binds, it is located deep in the lungs. Infection by the avian virus is thus difficult, and, when it does occur, the avian virus is not readily transmitted by sneezing or coughing.

Plasmodium falciparum, the parasitic protozoan that causes malaria, also relies on glycan binding to infect and colonize its host. Glycan-binding proteins of the parasitic form initially injected by the mosquito bind to the glycosaminoglycan heparin sulfate on the liver, initiating the parasite’s entry into the cell. On exiting from the liver later in its life cycle, the parasite invades red blood cells by using another glycan-binding protein to bind to the carbohydrate moiety of glycophorin, a prominent membrane glycoprotein in red blood cells. Developing means to disrupt the carbohydrate interactions between pathogens and host cells may prove to be clinically useful.