Figure 8.

Alignment of TPR domains of proteins that bind Hsp90 or Hsp70. Residues in bold are part of the TPR consensus and are required for the packing of adjacent TPR α-helices (helix A and helix B). TPR residues predicted to be involved in the formation of tight electrostatic interactions with the EEVD motif from the crystal structure of Hop TPR2A and TPR1 with the Hsp90 MEEVD and Hsp70 PTIEEVD, respectively, are outlined.²⁴ Residues underlined are predicted to form a peptide-binding pocket through tight electrostatic interactions based on the crystal structure of FKBP52 with the Hsp90 MEEVD.²⁷ The lysine residue, demarcated by an asterisk, is the TPR residue targeted in AIPL1(K265A). Circled residues are AIPL1 mutations in the TPR domain previously associated with pathogenesis and tested for Hsp90 binding in our yeast two-hybrid screen, including A197P, C239R, G262S, and W278X. The other mutations associated with pathogenesis tested in our screen (H82Y and R302L) are outside the region depicted.