Tags

Type your tag names separated by a space and hit enter

Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling.
Mol Cell Biol. 2007 Dec; 27(24):8658-69.MC

Abstract

Hormone-dependent transactivation by several of the steroid hormone receptors is potentiated by the Hsp90-associated cochaperone FKBP52, although not by the closely related FKBP51. Here we analyze the mechanisms of potentiation and the functional differences between FKBP51 and FKBP52. While both have peptidyl-prolyl isomerase activity, this is not required for potentiation, as mutations abolishing isomerase activity did not affect potentiation. Genetic selection in Saccharomyces cerevisiae for gain of potentiation activity in a library of randomly mutated FKBP51 genes identified a single residue at position 119 in the N-terminal FK1 domain as being a critical difference between these two proteins. In both the yeast model and mammalian cells, the FKBP51 mutation L119P, which is located in a hairpin loop overhanging the catalytic pocket and introduces the proline found in FKBP52, conferred significant potentiation activity, whereas the converse P119L mutation in FKBP52 decreased potentiation. A second residue in this loop, A116, also influences potentiation levels; in fact, the FKBP51-A116V L119P double mutant potentiated hormone signaling as well as wild-type FKBP52 did. These results suggest that the FK1 domain, and in particular the loop overhanging the catalytic pocket, is critically involved in receptor interactions and receptor activity.

Links

PMC Free PDF
PMC Free Full Text
Publisher Full Text

Authors+Show Affiliations

Riggs DL
Mayo Clinic Arizona, 13400 E. Shea Blvd., Scottsdale, AZ 85259, USA.
Cox MB
No affiliation info available
Tardif HL
No affiliation info available
Hessling M
No affiliation info available
Buchner J
No affiliation info available
Smith DF
No affiliation info available

MeSH

Amino Acid SequenceAnimalsCatalysisDrug SynergismMiceModels, MolecularMolecular Sequence DataMutant ProteinsMutationPeptidylprolyl IsomeraseProtein Structure, TertiaryRecombinant Fusion ProteinsSelection, GeneticSignal TransductionSteroidsStructure-Activity RelationshipTacrolimus Binding Proteins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17938211

Citation

Riggs, Daniel L., et al. "Noncatalytic Role of the FKBP52 Peptidyl-prolyl Isomerase Domain in the Regulation of Steroid Hormone Signaling." Molecular and Cellular Biology, vol. 27, no. 24, 2007, pp. 8658-69.
Riggs DL, Cox MB, Tardif HL, et al. Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling. Mol Cell Biol. 2007;27(24):8658-69.
Riggs, D. L., Cox, M. B., Tardif, H. L., Hessling, M., Buchner, J., & Smith, D. F. (2007). Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling. Molecular and Cellular Biology, 27(24), 8658-69.
Riggs DL, et al. Noncatalytic Role of the FKBP52 Peptidyl-prolyl Isomerase Domain in the Regulation of Steroid Hormone Signaling. Mol Cell Biol. 2007;27(24):8658-69. PubMed PMID: 17938211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling. AU - Riggs,Daniel L, AU - Cox,Marc B, AU - Tardif,Heather L, AU - Hessling,Martin, AU - Buchner,Johannes, AU - Smith,David F, Y1 - 2007/10/15/ PY - 2007/10/17/pubmed PY - 2007/12/19/medline PY - 2007/10/17/entrez SP - 8658 EP - 69 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 27 IS - 24 N2 - Hormone-dependent transactivation by several of the steroid hormone receptors is potentiated by the Hsp90-associated cochaperone FKBP52, although not by the closely related FKBP51. Here we analyze the mechanisms of potentiation and the functional differences between FKBP51 and FKBP52. While both have peptidyl-prolyl isomerase activity, this is not required for potentiation, as mutations abolishing isomerase activity did not affect potentiation. Genetic selection in Saccharomyces cerevisiae for gain of potentiation activity in a library of randomly mutated FKBP51 genes identified a single residue at position 119 in the N-terminal FK1 domain as being a critical difference between these two proteins. In both the yeast model and mammalian cells, the FKBP51 mutation L119P, which is located in a hairpin loop overhanging the catalytic pocket and introduces the proline found in FKBP52, conferred significant potentiation activity, whereas the converse P119L mutation in FKBP52 decreased potentiation. A second residue in this loop, A116, also influences potentiation levels; in fact, the FKBP51-A116V L119P double mutant potentiated hormone signaling as well as wild-type FKBP52 did. These results suggest that the FK1 domain, and in particular the loop overhanging the catalytic pocket, is critically involved in receptor interactions and receptor activity. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/17938211/Noncatalytic_role_of_the_FKBP52_peptidyl_prolyl_isomerase_domain_in_the_regulation_of_steroid_hormone_signaling_ L2 - https://journals.asm.org/doi/10.1128/MCB.00985-07?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -