Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40

Large peptidyl-prolyl cis/trans isomerases (PPIases) are important componen ts of the Hsp90 chaperone complex. In mammalian cells, either Cyp40, FKBP51 or FKBP52 is incorporated into these complexes. It has been suggested that members of this protein family exhibit both prolyl isomerase and chaperone activity. Here we define the structural and functional properties of the t hree mammalian large PPIases. We find that in all cases two PPIase monomers bind to an Hsp90 dimer. However, the affinities of the PPIases are differe nt with FKBP52 exhibiting the strongest interaction and Cyp40 the weakest. Furthermore, in the mammalian system, in contrast to the yeast system, the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. Interestingly, Cyp40 and FKBP51 are the more pote nt chaperones. Thus, it seems that both the affinity for Hsp90 and the diff erences in their chaperone properties, which may reflect their interaction with the non-native protein in the Hsp90 complex, are critical for the sele ctive incorporation of a specific large PPIase. (C) 2001 Academic Press.