Differential conformational dynamics in the closely homologous FK506-binding domains of FKBP51 and FKBP52

As co-chaperones of Hsp90 (heat-shock protein 90), FKBP51 (FK506-binding protein of 51 kDa) and FKBP52 (FK506-binding protein of 52 kDa) act as antagonists in regulating the hormone affinity and nuclear transport of steroid receptor complexes. Exchange of Leu(119) in FKBP51 for Pro(119) in FKBP52 has been shown to largely reverse the steroid receptor activities of FKBP51 and FKBP52. To examine whether differences in conformational dynamics/plasticity might correlate with changes in the reported receptor activities, (15)N-NMR relaxation measurements were carried out on the N-terminal FKBP domains of FKBP51 and FKBP52 as well as their residue-swapped variants. Both proteins exhibit a similar pattern of motion in the picosecond–nanosecond timeframe as well as a small degree of (15)N line-broadening, indicative of motion in the microsecond–millisecond timeframe, in the β(3a) strand of the central sheet. Only the FKBP51 domain exhibits much larger line-broadening in the adjacent β(3) bulge (40′s loop of FKBP12) and throughout the long β(4)–β(5) loop (80′s loop of FKBP12). The L119P mutation at the tip of the β(4)–β(5) loop completely suppressed the line-broadening in this loop while partially suppressing the line-broadening in the neighbouring β(2) and β(3a) strands. The complementary P119L and P119L/P124S variants of FKBP52 yielded similar patterns of line-broadening for the β(4)–β(5) loop as that for FKBP51, although only 20% and 60% as intense respectively. However, despite the close structural similarity in the packing interactions between the β(4)–β(5) loop and the β(3a) strand for FKBP51 and FKBP52, the line-broadening in the β(3a) strand is unaffected by the P119L or P119L/P124S mutations in FKBP52.