Definition
Glycoproteins are protein containing one or more covalently linked carbohydrates of various types, from monosaccharides to branched polysaccharides, including glycosylphosphatidylinositol (GPI), glycosaminoglycans (GAG). A number of glycoproteins are produced industrially by genetic engineering techniques for use as drugs; among them are erythropoietin, interferons, colony stimulating factors, and blood-clotting factors.
Discovery
The structures of the carbohydrate chains present in fragments of a large-MW glycoprotein, epiglycanin, were studied by Codington et al., in 1975. All chains are attached to a single polypeptide chain by O-glycosyl bonds involving a 2-acetamido-2-deoxygalactose residue and a serine or threonine residue. It is suggested that the native molecule of epiglycanin of MW 500,000 contains more than 500 carbohydrate chains attached to a single polypeptide chain of similar to 1,300 amino acid units 1. Glycoprotein Fragments, Cys-CD36 (139-155), represents part of the epitope that binds the monoclonal anti-CD36 anti-body OKM5. It enhanced binding of CD36 to thrombospondin and augmented ADP-induced and collagen-induced aggregation in platelet-rich plasma. Glycoprotein Fragments, CD36 (93-110)-Cys, blocked binding of CD36 to immobilized thrombospondin and partially inhibited collagen-induced platelet aggregation 2. The FSH, TSH, LH, and hCG are glycoprotein hormones sharing a common a subunit. Residues 32-46 of this a subunit have been identified as a receptor binding domain. This peptide fragment inhibited FSH and LH/hCG binding to their respective calf testis membrane receptors with IC50 of 36 µM and 54 µM, respectively 3.
Structural Characteristics
In most glycoproteins, the carbohydrate is linked to the polypeptide backbone by either N- or O-glycosidic bonds. A different kind of bond is found in glycoproteins that are anchored in cell membranes by a special carbohydrate-containing compound, GPI, which is attached to the C-terminal amino acid of the protein. A single glycoprotein may contain more than one type of carbohydrate-peptide linkage. N-linked units are typically found in plasma glycoproteins, in ovalbumin, in many enzymes and in immunoglobulins. O-linked units are found in mucins; collagens; and proteoglycans, including chondroitin sulfates, dermatan sulfate, and heparin. Mucin-type glycoprotein material was fractionated by gel filtration after cleavage from viable TA3-Ha mouse mammary adenocarcinoma ascites cells by a modified trypsin. The macromolecular glycoproteins present in each cell fraction were characterized by electron microscopy of metal-contrasted replicas as highly asymmetric rods. Investigation of one fraction gave close agreement for length by electron microscopic measurements and for a length calculated for a single polypeptide backbone model from a MW value by short column sedimentation equilibrium, amino acid composition, and percentage of protein 4.
Mode of Action
The MDR1 (multidrug resistance) gene product P-glycoprotein is a membrane protein, which functions as an ATP-dependent exporter of xenobiotics from cells. It has role in the development of MDR of cultured tumor cells against various anticancer agents. Since P-glycoprotein has broad substrate specificity, it determines disposition of a broad variety of drugs. Induction and inhibition of P-glycoprotein are new mechanisms for drug interactions in humans. MDR1 polymorphisms influence P-glycoprotein tissue expression, drug disposition, and treatment outcome and disease risk 5.
The major neutralizing antigen of bovine rotavirus (BRV) is an outer surface glycoprotein with an approximate MW of 38,200. Surface glycoprotein was analyzed whether this fragment had the ability to induce the production of neutralizing antibodies. Upon immunization of mice, the bovine serum albumin-conjugated 14,000-MW fragment, the unconjugated 14,000-MW fragment, and the native glycoprotein all induced a similar neutralizing antibody response. Results suggest that the 14,000-MW fragment may represent not only a biologically active region but also an immunodominant area of the glycoprotein 6.
Functions
Biological role: Glycoproteins and fragments are demonstrated in diverse and vital cellular functions. These have been reported to include ektobiological activities of cells, such as contact inhibition of growth, cellular adhesion, transplantation rejection, tumor-specific antigenic activity, and suppression of antigenie activity. Cell surface glycoproteins may also participate in active transport and contain blood-specific groupings and recognition sites for viruses and plant agglutinins 4.
In the immune system glycoproteins are important for white blood cell recognition, glycoproteins in the immune system are: molecules such as antibodies, which interact directly with antigens molecules of the major histocompatibility complex, which are expressed on the surface of cells and interact with T cells as part of the adaptive immune response.
Adherence to the endothelium: Glycoprotein IIb/IIIa, an integrin found on platelets required for normal platelet aggregation and adherence to the endothelium.
Structural glycoproteins occur in connective tissue. These help bind together the fibers, cells, and ground substance of connective tissue. They may also help components of the tissue bind to inorganic substances, such as calcium in bone.
Viral proteins, Glycoprotein-41 (gp41) and glycoprotein-120 (gp120) are HIV viral coat proteins,
gp120 binds to the CD4+ molecule on helper T-cells during infection. Gp41, embedded in the outer envelope of HIV that anchors gp120. gp41 plays a key role in HIVs entry into CD4+ T-cells by facilitating the fusion of the viral and cell membranes.
Hormones, several important hormones are glycoproteins that include: Follicle-stimulating hormone, Luteinizing hormone, Thyroid-stimulating hormone, Human chorionic gonadotropin
Alpha-fetoprotein, Erythropoietin (EPO).
References
1. Codington JF, Linsley KB, Jeanloz RW, Irimura T, Osawa T (1975). Immunochemical and chemical investigations of the structure of glycoprotein fragments obtained from epiglycanin, a glycoprotein at the surface of the TA3-Ha cancer cell. Carbohydr Res., 40(1):171-182.
2. Leung LL, Li WX, McGregor JL, Albrecht G, Howard RJ (1992). CD36 peptides enhance or inhibit CD36-thrombospondin binding. A two-step process of ligand-receptor interaction. J. Biol. Chem., 267(25):18244-18250.
3. Leng N, Grasso P, Deziel MR, Reichert LE Jr (1995). A synthetic peptide corresponding to glycoprotein hormone alpha subunit residues 32-46 inhibits gonadotropin binding to receptor. Pept. Res., 8:272-277.
4. Slayter HS, Codington JF (1973). Size and Configuration of Glycoprotein Fragments Cleaved from Tumor Cells by Broteolysis. J Biol Chem., 248(10):3405-3410.
5. Fromm MF (2002). The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Advanced Drug Delivery Reviews., 54(10):1295-1310.
6. Sabara M, Barrington A, Babiuk LA (1985). Immunogenicity of a Bovine Rotavirus Glycoprotein Fragment. J Virol., 56(3):1037-1040.