An unexpected extended conformation for the third TPR motif of the peroxinPEX5 from Trypanosoma brucei

A number of helix-rich protein motifs are involved in a variety of critical protein-protein interactions in living cells. One of these is the tetratri co peptide repeat (TPR) motif that is involved, amongst others, in cell cyc le regulation, chaperone function and post-translation modifications. So fa r, these helix-rich TPR motifs have always been observed to be a compact un it of two helices interacting with each other in antiparallel fashion. Here , we describe the structure of the first three TPR-motifs of the peroxin PE X5 from Trypanosoma brucei, the causative agent of sleeping sickness. Perox ins are proteins involved in peroxisome, glycosome and glyoxysome biogenesi s. PEX5 is the receptor of the proteins targeted to these organelles by the "peroxisomal targeting signal-1", a C-terminal tripeptide called PTS-1. Th e first two of the three TPR-motifs of T.brucei PEX5 appear to adopt the ca nonical antiparallel helix hairpin structure. In contrast, the third TPR mo tif of PEX5 has a dramatically different conformation in our crystals: the two helices that were supposed to form a hairpin are folded into one single 44 Angstrom long continuous helix. Such a conformation has never been obse rved before for a TPR motif. This raises interesting questions including th e potential functional importance of a "jack-knife" conformational change i n TPR motifs. (C) 2001 Academic Press.