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Article

Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity

1
Border Biomedical Research Center and Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
2
Department of Chemistry and Biochemistry, Kettering University, Flint, MI 48504, USA
3
Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(21), 5346; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215346
Received: 30 September 2019 / Revised: 24 October 2019 / Accepted: 25 October 2019 / Published: 28 October 2019
Previous studies demonstrated that the 52-kDa FK506-binding protein (FKBP52) proline-rich loop is functionally relevant in the regulation of steroid hormone receptor activity. While zebra fish (Danio rerio; Dr) FKBP52 contains all of the analogous domains and residues previously identified as critical for FKBP52 potentiation of receptor activity, it fails to potentiate activity. Thus, we used a cross-species comparative approach to assess the residues that are functionally critical for FKBP52 function. Random selection of gain-of-function DrFKBP52 mutants in Saccharomyces cerevisiae identified two critical residues, alanine 111 (A111) and threonine 157 (T157), for activation of receptor potentiation by DrFKBP52. In silico homology modeling suggests that alanine to valine substitution at position 111 in DrFKBP52 induces an open conformation of the proline-rich loop surface similar to that observed on human FKBP52, which may allow for sufficient surface area and increased hydrophobicity for interactions within the receptor–chaperone complex. A second mutation in the FKBP12-like domain 2 (FK2), threonine 157 to arginine (T157R), also enhanced potentiation, and the DrFKBP52-A111V/T157R double mutant potentiated receptor activity similar to human FKBP52. Collectively, these results confirm the functional importance of the FKBP52 proline-rich loop, suggest that an open conformation on the proline-rich loop surface is a predictor of activity, and highlight the importance of an additional residue within the FK2 domain. View Full-Text
Keywords: Danio rerio; zebra fish; steroid hormone receptor; cochaperone; FKBP52; heat shock protein 90 (Hsp90); Hsp70; proline-rich loop; androgen receptor; glucocorticoid receptor; progesterone receptor Danio rerio; zebra fish; steroid hormone receptor; cochaperone; FKBP52; heat shock protein 90 (Hsp90); Hsp70; proline-rich loop; androgen receptor; glucocorticoid receptor; progesterone receptor
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MDPI and ACS Style

Harris, D.C.; Garcia, Y.A.; Samaniego, C.S.; Rowlett, V.W.; Ortiz, N.R.; Payan, A.N.; Maehigashi, T.; Cox, M.B. Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity. Int. J. Mol. Sci. 2019, 20, 5346. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215346

AMA Style

Harris DC, Garcia YA, Samaniego CS, Rowlett VW, Ortiz NR, Payan AN, Maehigashi T, Cox MB. Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity. International Journal of Molecular Sciences. 2019; 20(21):5346. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215346

Chicago/Turabian Style

Harris, Diondra C., Yenni A. Garcia, Cheryl S. Samaniego, Veronica W. Rowlett, Nina R. Ortiz, Ashley N. Payan, Tatsuya Maehigashi, and Marc B. Cox 2019. "Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity" International Journal of Molecular Sciences 20, no. 21: 5346. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215346

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