Evolutionary design of glutathione-linked proteins in vivo and in vitro based on sampling of modules from pre-existing structures

Structural studies suggest that naturally occurring proteins represent a li mited number of folds. It would appear that the evolution of novel protein functions to a large extent involves redesign of stable peptide scaffolds b y means of combinatorial protein chemistry. Naturally evolved proteins as w ell as proteins redesigned by recombinant DNA techniques can, therefore, be considered as assembled from structural modules derived from a 'space' com posed of segments of primary structure, elements of secondary structure: do mains, higher-order tertiary or quaternary assemblies. Glutathione-linked p roteins illustrate this paradigm at all structural levels: primary, seconda ry, tertiary, and quaternary. Some natural proteins obviously have a common ancestry, but from the perspective of protein design it is irrelevant if g lutathione-linked proteins have emerged from divergent or convergent evolut ion. Mimicking the redesign of proteins in nature is a powerful approach to the engineering np of enzymes for novel functions. (C) 2001 Elsevier Scien ce Ireland Ltd. All rights reserved.