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

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 critic...

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Autores principales: Harris, Diondra C., Garcia, Yenni A., Samaniego, Cheryl Storer, Rowlett, Veronica W., Ortiz, Nina R., Payan, Ashley N., Maehigashi, Tatsuya, Cox, Marc B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862696/
https://www.ncbi.nlm.nih.gov/pubmed/31661769
http://dx.doi.org/10.3390/ijms20215346
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author Harris, Diondra C.
Garcia, Yenni A.
Samaniego, Cheryl Storer
Rowlett, Veronica W.
Ortiz, Nina R.
Payan, Ashley N.
Maehigashi, Tatsuya
Cox, Marc B.
author_facet Harris, Diondra C.
Garcia, Yenni A.
Samaniego, Cheryl Storer
Rowlett, Veronica W.
Ortiz, Nina R.
Payan, Ashley N.
Maehigashi, Tatsuya
Cox, Marc B.
author_sort Harris, Diondra C.
collection PubMed
description 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.
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spelling pubmed-68626962019-12-05 Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity Harris, Diondra C. Garcia, Yenni A. Samaniego, Cheryl Storer Rowlett, Veronica W. Ortiz, Nina R. Payan, Ashley N. Maehigashi, Tatsuya Cox, Marc B. Int J Mol Sci Article 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. MDPI 2019-10-28 /pmc/articles/PMC6862696/ /pubmed/31661769 http://dx.doi.org/10.3390/ijms20215346 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Harris, Diondra C.
Garcia, Yenni A.
Samaniego, Cheryl Storer
Rowlett, Veronica W.
Ortiz, Nina R.
Payan, Ashley N.
Maehigashi, Tatsuya
Cox, Marc B.
Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity
title Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity
title_full Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity
title_fullStr Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity
title_full_unstemmed Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity
title_short Functional Comparison of Human and Zebra Fish FKBP52 Confirms the Importance of the Proline-Rich Loop for Regulation of Steroid Hormone Receptor Activity
title_sort functional comparison of human and zebra fish fkbp52 confirms the importance of the proline-rich loop for regulation of steroid hormone receptor activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862696/
https://www.ncbi.nlm.nih.gov/pubmed/31661769
http://dx.doi.org/10.3390/ijms20215346
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