Localization of the Chaperone Domain of FKBP52

Pirkl, Franziska; Fischer, Eugen; Modrow, Susanne; Büchner, Johannes

doi:10.1074/jbc.m102595200

Cited by 61 publications

(50 citation statements)

References 56 publications

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“…The FK1 domain is responsible for the PPIase activity of FKBP52, whereas the FK2 domain shows no PPIase activity (27,28). Detailed structural information for FK1 has been reported (17).…”

Section: Methodsmentioning

confidence: 99%

3D structure of human FK506-binding protein 52: Implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex

Li²,

Liu³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

154

170

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FK506-binding protein 52 (FKBP52), which binds FK506 and possesses peptidylprolyl isomerase activity, is an important immunophilin involved in the heterocomplex of steroid receptors with heat-shock protein 90. Here we report the crystal structures of two overlapped fragments [N(1-260) and C(145-459)] of FKBP52 and the complex with a C-terminal pentapeptide from heat-shock protein 90. Based on the structures of these two overlapped fragments, the complete putative structure of FKBP52 can be defined. The structure of FKBP52 is composed of two consecutive FKBP domains, a tetratricopeptide repeat domain and a short helical domain beyond the final tetratricopeptide repeat motif. Key structural differences between FKBP52 and FKBP51, including the relative orientations of the four domains and some important residue substitutions, could account for the differential functions of FKBPs.

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“…The FK1 domain is responsible for the PPIase activity of FKBP52, whereas the FK2 domain shows no PPIase activity (27,28). Detailed structural information for FK1 has been reported (17).…”

Section: Methodsmentioning

confidence: 99%

3D structure of human FK506-binding protein 52: Implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex

Li²,

Liu³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

154

170

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“…Another possibility is that co-chaperones continually modulate GRP94 activity, and they are lost during purification of the protein. The cytosolic HSP90 exists in a complex with other proteins, such as p23 and FKBP52 (50,51), and it is possible that analogous proteins are bound to GRP94 in the endoplasmic reticulum.…”

Section: Figmentioning

confidence: 99%

Radicicol-sensitive Peptide Binding to the N-terminal Portion of GRP94

Vogen¹,

Gidalevitz²,

Biswas³

et al. 2002

Journal of Biological Chemistry

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GRP94 is a molecular chaperone that carries immunologically relevant peptides from cell to cell, transferring them to major histocompatibility proteins for presentation to T cells. Here we examine the binding of several peptides to recombinant GRP94 and study the regulation and site of peptide binding. We show that GRP94 contains a peptide-binding site in its N-terminal 355 amino acids. A number of peptides bind to this site with low on-and off-rates and with specificity that is distinct from that of another endoplasmic reticulum chaperone, BiP/GRP78. Binding to the N-terminal fragment is sufficient to account for the peptide binding activity of the entire molecule. Peptide binding is inhibited by radicicol, a known inhibitor of the chaperone activities of HSP90-family proteins. However, the peptide-binding site is distinct from the radicicol-binding pocket, because both can bind to the N-terminal fragment simultaneously. Furthermore, peptide binding does not cause the same conformational change as does binding of radicicol. When the latter binds to the N-terminal domain, it induces a conformational change in the downstream, acidic domain of GRP94, as measured by altered gel mobility and loss of an antibody epitope. These results relate the peptide-binding activity of GRP94 to its other function as a chaperone.

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“…However, GR and FKBP51/52 evolved only in higher organisms, and the immunophilins also exhibit hsp90-independent features (15,38,39). To test the hsp90 dependence of the FKBP51-inhibitory effect on GR in our mammalian reporter system, we replaced the positively charged amino acids lysine 352 and arginine 356 with alanines in the hsp90-interacting TPR repeat motif, (see Fig.…”

Section: Fkbp51 and Fkbp52 Act Differentially On Gr In Mamma-mentioning

confidence: 99%

“…White box, PPIase (39,50); gray box, second FKBP12 homology domain (39,50,51); dark gray box, TPR domain (containing three repeats, (52); black box, putative calmodulin binding domain (Cal) (53). B, structure of the chimera constructed.…”

Section: Fig 6 the Ppiase Domain Of Fkbp51 Is Essential For Its Inhmentioning

confidence: 99%

FK506-binding Proteins 51 and 52 Differentially Regulate Dynein Interaction and Nuclear Translocation of the Glucocorticoid Receptor in Mammalian Cells

Wochnik

Rüegg

Abel

et al. 2005

Journal of Biological Chemistry

572

495

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We used a cellular system to elucidate the molecular determinants of the large immunophilin FK506-binding proteins (FKBP)51 and -52 for their action on the glucocorticoid receptor in mammalian cells. Increasing the levels of FKBP51 reduced the transcriptional activity of the receptor, as reported. Elevated levels of FKBP52 per se showed no effect but mitigated the inhibition of the receptor induced by FKBP51. We discovered that nuclear translocation of the glucocorticoid receptor was delayed by FKBP51. This correlates with the reduced interaction of FKBP51 with the motor protein dynein compared with FKBP52. From mutational analyses, we concluded that three features of the immunophilins are required for efficient receptor signaling in mammalian cells: hsp90 interaction, dynein association, and peptidylprolyl isomerase (PPIase) enzyme activity. The relevance of dynein for receptor function was substantiated by several experiments: 1) coexpression of dynamitin, which disrupts the transport complex and reduces receptor activity; 2) coexpression of the PPIase domain fragment of FKBP52, which is known to disrupt interaction of the receptor to dynein and reduce glucocorticoid receptor function, in contrast to the corresponding fragment of FKBP51; and 3) swapping of the PPIase domains FKBP51 and FKBP52, which reverses the respective activity. We concluded from our results that the mechanisms of the regulatory system FKBP51/FKBP52 discovered in yeast also operate in mammals to modulate hormone binding of the receptor. In addition, differential regulation of dynein association and nuclear translocation contributes to the effects of the two immunophilins on the glucocorticoid receptor in mammals.

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Localization of the Chaperone Domain of FKBP52

Cited by 61 publications

References 56 publications

3D structure of human FK506-binding protein 52: Implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex

3D structure of human FK506-binding protein 52: Implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex

Radicicol-sensitive Peptide Binding to the N-terminal Portion of GRP94

FK506-binding Proteins 51 and 52 Differentially Regulate Dynein Interaction and Nuclear Translocation of the Glucocorticoid Receptor in Mammalian Cells

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