Immunoglobulin fold

Fig. 3. Representation of the nine principal folds which recur in protein stmctures, where the codes of the representative proteins taken from the Brookhaven Protein Data Bank (PDB) (17) are given in parentheses (18) (1) globin (Ithb) (2) trefoil (lilb) (3) up—down (256b) (4) immunoglobulin folds...

The immunoglobulin fold is best described as two antiparallel sheets packed tightly against each other... 

IgG antibody molecules are composed of two light chains and two heavy chains joined together by disulfide bonds. Each light chain has one variable domain and one constant domain, while each heavy chain has one variable and three constant domains. All of the domains have a similar three-dimensional structure known as the immunoglobulin fold. The Fc stem of the molecule is formed by constant domains from each of the heavy chains, while two Fab arms are formed by constant and variable domains from both heavy and light chains. The hinge region between the stem and the arms is flexible and allows the arms to move relative to each other and to the stem. 

Class 1 and class II MHC molecules bind peptide antigens and present them at the cell surface for interaction with receptors on T cells. The extracellular portion of these molecules consists of a peptide-binding domain formed by two helical regions on top of an eight-stranded antiparallel p sheet, separated from the membrane by two lower domains with immunoglobulin folds. These domains are differently disposed between the two protein subunits in class I and class II molecules. 

With the realization that there are only a limited number of stable folds and many unrelated sequences that have the same fold, biologically oriented computer scientists started to address what is called the inverse folding problem namely, which sequence patterns are compatible with a specific fold If this question can be answered, such patterns could be used to search through the genome sequence databases and extract those sequences that have a specific fold, such as the cx/p barrel or the immunoglobulin fold. 

From the results reported to date, it seems that the manner in which haptens are attached to carrier proteins leads to significant differences in certain cases. Clearly, haptens designed with aromatic moieties between the linkage to the immunogenic carrier protein and the TSA motif often have better antibody recognition. Recently, Hilvert pointed out that on both micro and macro levels, mechanistic improvements arise as a function of time. The differences in time scales for the evolution of natural enzymes and antibodies — millions of years versus weeks or months — also appear to be an explanation of the low efficiency of antibody catalysts. He also highlighted that the unique immunoglobulin fold has not been adopted by nature as one of the common scaffolds on which to build enzyme catalytic machinery. Therefore, antibody structure itself places limitations on the kind of reactions amenable to catalysis. 

The fundamental structure of immunoglobulins was first established by Gerald Edelman and Rodney Porter. Each chain is made up of identifiable domains some are constant in sequence and structure from one IgG to the next, others are variable. The constant domains have a characteristic structure known as the immunoglobulin fold, a well-conserved structural motif in the all /3 class of proteins (Chapter 4). There are three of these constant domains in each heavy chain and one in each light chain. The heavy and light chains also have one variable domain each, in which most of the variability in amino acid residue sequence is found. The variable domains associate to create the antigen-binding site (Fig. 5-24). 

From Guss and Freeman.116 (B) Ribbon drawing of immunoglobulin fold. This is a common structure in domains of the immunoglobulins and in many other extracellular proteins. Two layers of antiparallel (3 sheet are stacked face to face to form a flattened barrel. One disulfide bridge is always present and is represented as a thick rod. From J. Richardson.117 (C) Five tandem fibronectin type III domains. 

Bork, P., Holm, L., and Sander, C. (1994). The immunoglobulin fold. Structural classificadon, sequence patterns and common core. J. Mol. Biol. 242, 309-320. 

The three-dimensional structure of the PapD periplasmic chaperone that forms transient complexes with pilus subunit proteins has been solved by Holmgren and Branden (1989). PapD consists of two globular domains oriented in the shape of a boomerang (Fig. 2). Each domain is a /3-barrel structure formed by two antiparallel /8-pleated sheets that have a topology similar to an immunoglobulin fold. The relationship between PapD and other immunoglobulin-like proteins is discussed in Section IV,C. 

Fig. 5. Schematic representation of a/3-barrel. which forms the skeleton of the immunoglobulin fold domain. Note that the /3 strands run antiparallel and are connected by loops that cluster at the ends of the barrel.

The recently reported structure of the human growth hormonebinding protein (hGHbp) complexed with its ligand has shown that it is a member of the cytokine receptor superfamily and makes use of the immunoglobulin fold for molecular recognition (De Vos et al., 1992). 

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