Structure of TPR domain-peptide complexes: Critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine

The adaptor protein Hop mediates the association of the molecular chaperone s Hsp70 and Hsp90. The TPR1 domain of Hop specifically recognizes the C-ter minal heptapeptide of Hsp70 while the TPR2A domain binds the C-terminal pen tapeptide of Hsp90. Both sequences end with the motif EEVD. The crystal str uctures of the TPR-peptide complexes show the peptides in an extended confo rmation, spanning a groove in the TPR domains. Peptide binding is mediated by electrostatic interactions with the EEVD motif, with the C-terminal aspa rtate acting as a two-carboxylate anchor, and by hydrophobic interactions w ith residues upstream of EEVD. The hydrophobic contacts with the peptide ar e critical for specificity. These results explain how TPR domains participa te in the ordered assembly of Hsp70-Hsp90 multichaperone complexes.