Peroxisomal targeting signal-1 recognition by the TPR domains of human PEX5

Many proteins contain targeting signals within their sequences that specify their delivery to particular organelles. The peroxisomal targeting signal- 1 (PTS1) is a C-terminal tripeptide that is sufficient to direct proteins i nto peroxisomes. The PTS1 sequence closely approximates Ser-Lys-Leu-COO-. P EX5, the receptor for PTSI, interacts with the signal via a series of tetra tricopeptide repeats (TPRs) within its C-terminal half. Here we report the crystal structure of a fragment of human PEX5 that includes all seven predi cted TPR motifs in complex with a pentapeptide containing a PTS1 sequence. Two clusters of three TPRs almost completely surround the peptide, while a hinge region, previously identified as TPR4 forms a distinct structure that enables the two sets of TPRs to form a single binding site. This structure reveals the molecular basis for PTS1 recognition and demonstrates a novel mode of TPR-peptide interaction.