In memoriam: Reflections on Fred Richards (1925–2009)

Abstract

Fred Richards made a remarkable discovery right at the start of his scientific career. In his year of postdoctoral research (1954–1955) at the Carlsberg Laboratory, Copenhagen, Fred studied the digestion of RNase A (bovine pancreatic ribonuclease A) by subtilisin, a bacterial protease. He found evidence for a surprising intermediate in the digestion process: see below. Later, in his own lab at Yale, Fred characterized the intermediate (RNase S) by separating it into two parts, a 20-residue peptide (S-pep) and a 104-residue protein moiety (S-prot), and he found that enzymatic activity is lost when the two chains are separated. Remarkably, S-pep and S-prot combine spontaneously when they are mixed together and the product is active enzyme. This result1 immediately clarified how peptide hormones might activate their protein receptors. Because S-prot is only weakly folded and S-pep is nearly structureless, whereas RNase S is a stable, well-folded protein, the reaction S-pep + S-prot = RNase S became a standard system for folding studies and helped to open up the study of the mechanism of protein folding.