Amino acid sequence alignment of bacterial and mammalian pancreatic serine proteases based on topological equivalences

Abstract

The three-dimensional structures of the bacterial serine proteases SGPA, SGPB, and α-lytic protease have been compared with those of the pancreatic enzymes α-chymotrypsin and elastase. This comparison shows that ~60% (55–64%) of the α-carbon atom positions of the bacterial serine proteases are topologically equivalent to the α-carbon atom positions of the pancreatic enzymes. The corresponding value for a comparison of the bacterial enzymes among themselves is ~84%. The results of these topological comparisons have been used to deduce an experimentally sound sequence alignment for these several enzymes. This alignment shows that there is extensive tertiary structural homology among the bacterial and pancreatic enzymes without significant primary sequence identity (<21%). The acquisition of a zymogen function by the pancreatic enzymes is accompanied by two major changes to the bacterial enzymes' architecture: an insertion of 9 residues to increase the length of the N-terminal loop, and one of 12 residues to a loop near the activation salt bridge. In addition, in these two enzyme families, the methionine loop (residues 164–182) adopts very different conformations which are associated with their altered substrate specificities.