A folding space odyssey

Abstract

Most of us who teach protein structure have very likely stood in front of a class at some point and confidently stated that any two naturally occurring proteins displaying 40% sequence identity will be homologous and thus possess the same fold. A paper by Roessler et al. (1) in a recent issue of PNAS has definitively overturned this basic tenet by demonstrating that a pair of protein homologues displaying 40% identity exhibit markedly different folds. These proteins are both repressors of the Cro family and were identified in prophage sequences present in the genomes of the bacterial species, Pseudomonas fluorescens (Pfl 6) and Xylella fastidiosa (Xfaso 1). The atomic resolution structures of these proteins, solved by Roessler et al. using x-ray crystallography, reveal a similar N-terminal helix–turn–helix but widely diverging C-terminal regions; Xfaso 1 displays an all-helical monomeric fold, whereas the Pfl 6 C terminus forms an intertwined β-sheet dimer (Fig. 1 A). The conclusion that these proteins are descended from a common ancestor is strongly supported. An alignment of homologues of each of these protein shows that many positions are conserved across both groups of proteins even in the C-terminal region where the structures diverge (Fig. 1 B). This conservation pattern argues against a distinct C terminus being placed onto one of these proteins through a nonhomologous recombination event. The genomic context of the genes encoding these proteins with respect to other surrounding phage genes is also highly conserved, which implies a common ancestry and function. Homologous proteins with 40% sequence identity and different folds. (A) The atomic resolution structures of Pfl 6 and Xfaso 1 as solved by x-ray crystallography are shown. The helix–turn–helix motif, which is seen in both proteins, is colored in red. The structurally divergent regions are shown in green (Pfl 6) and in blue …