Biosynthesis of Antibodies and Molecular Chaperones

Abstract

The idea that antibody molecules may require helper molecules to gain their functional conformation is not new, but originated at a time when only little was known about the structure of antibodies. Landsteiner and others had shown that large numbers of antibodies could be produced by the vertebrate host although it was not clear how these molecules could react with so many different antigens (Landsteiner 1945). As an expansion of the original instruction theories, which said that antibodies were directly molded by the antigen, Burnet proposed in 1941 that it was the function of the antigen to stimulate an adaptive modification of those enzymes necessary for antibody synthesis, such that a unique protein molecule with a specific binding site would result (Burnet 1941). However, these theories were proven false by the demonstration that denatured antibodies, which were allowed to refold in vitro, did not require the presence of antigen to obtain their specific binding property (Haber 1964; Whitney and Tanford 1965). From Anson’s observations that denatured hemoglobin could be converted back into native protein (Anson 1945), it became obvious that the amino acid sequence contained all the information necessary to acquire the correct three-dimensional structure of the corresponding protein. Nevertheless, it is not yet possible to predict a three-dimensional structure directly from primary sequence information (Jaenicke 1988). The notion, however, that protein folding is a spontaneous self-organized process was so strong that — at least in the beginning of the chaperone research era — many molecular biologists refused to believe in the existence of special molecules that support such processes in the cell.