Immunoglobulin disulfide bridges: theme and variations.

Abstract

Prelude There are two types of disulfide bridges in immunoglobulins. One is the conserved intrachain bridge, spanning about 60 to 70 amino acid residues and found, as a monotonous theme, in every immunoglobulin domain. Buried deep between the opposing ~3-sheets, these bridges are shielded from solvent and, ordinarily, can be reduced only in the presence of denaturing agents. In contrast, the remaining disulfide bridges- interchain as well as occasional extra intrachain bonds- form a set of variations, differing in number and location according to immunoglobulin class and species, apparently constrained only by the necessity of conforming to the overall structure of the immunoglobulin fold. The latter bridges are typically located on the surface of the molecule, external to the ~3-sheets; they are accessible to solvent and are usually relatively easily reduced. Although their presence may impart special properties to certain immunoglobulin classes, the interchain disulfide bridges are not required for chain association, noncovalent forces generally being adequate for this task (see reviews by Beale & Feinstein, 1976, and Amzel & Poljak, 1979). The presence of buried conserved and superficial nonconserved disulfide bridges is also a characteristic feature of other extracellular proteins (Thornton, 1981). In historical context, recognition of the existence (Edelman, 1959; Edelman & Poulik, 1961), number and location (Nisonoff et al., 1961; Palmer and Nisonoff, 1964), and lability to reduction (Porter, 1962; Fleischman et al., 1963) of the interchain bridges in immunoglobulins played a crucial role in the establishment of the familiar four-chain model. In this article, I shall discuss some of the work carried out in my laboratory that bears on the general subject of the disulfide bridges in immunoglobulins. Partly by design, but mostly by accident, investigations of disulfide bridges have recurred in my research from the time I was a medical student at Yale, working in the laboratory of Fred Richards on the reduction and reoxidation of the disulfide bonds of ribonuclease (Steiner, t959). In the Porter laboratory, I studied patterns of interchain disulfide bonds in rabbit and human IgG. When I came to MIT, I drew on these experiences to work out a method for preparing heavy-atom derivatives of immunoglobulins in which mercuric ions are inserted into the interchain disulfide bridges. This was followed by the investigation of a crystallizable immunoglobulin strangely deficient in interchain bonds. Very recently, we have found that the light chains of bullfrog immunoglobulins have apparently replaced their bridge to the heavy