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FK506-Binding Protein 2 Participates in Proinsulin Folding
Apart from chaperoning, disulfide bond formation, and downstream processing, the molecular sequence of proinsulin folding is not completely understood. Proinsulin requires proline isomerization for correct folding. Since FK506-binding protein 2 (FKBP2) is an ER-resident proline isomerase, we hypothe...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9855983/ https://www.ncbi.nlm.nih.gov/pubmed/36671537 http://dx.doi.org/10.3390/biom13010152 |
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author | Hoefner, Carolin Bryde, Tenna Holgersen Pihl, Celina Tiedemann, Sylvia Naiga Bresson, Sophie Emilie Hotiana, Hajira Ahmed Khilji, Muhammad Saad Santos, Theodore Dos Puglia, Michele Pisano, Paola Majewska, Mariola Durzynska, Julia Klindt, Kristian Klusek, Justyna Perone, Marcelo J. Bucki, Robert Hägglund, Per Mårten Gourdon, Pontus Emanuel Gotfryd, Kamil Urbaniak, Edyta Borowiak, Malgorzata Wierer, Michael MacDonald, Patrick Edward Mandrup-Poulsen, Thomas Marzec, Michal Tomasz |
author_facet | Hoefner, Carolin Bryde, Tenna Holgersen Pihl, Celina Tiedemann, Sylvia Naiga Bresson, Sophie Emilie Hotiana, Hajira Ahmed Khilji, Muhammad Saad Santos, Theodore Dos Puglia, Michele Pisano, Paola Majewska, Mariola Durzynska, Julia Klindt, Kristian Klusek, Justyna Perone, Marcelo J. Bucki, Robert Hägglund, Per Mårten Gourdon, Pontus Emanuel Gotfryd, Kamil Urbaniak, Edyta Borowiak, Malgorzata Wierer, Michael MacDonald, Patrick Edward Mandrup-Poulsen, Thomas Marzec, Michal Tomasz |
author_sort | Hoefner, Carolin |
collection | PubMed |
description | Apart from chaperoning, disulfide bond formation, and downstream processing, the molecular sequence of proinsulin folding is not completely understood. Proinsulin requires proline isomerization for correct folding. Since FK506-binding protein 2 (FKBP2) is an ER-resident proline isomerase, we hypothesized that FKBP2 contributes to proinsulin folding. We found that FKBP2 co-immunoprecipitated with proinsulin and its chaperone GRP94 and that inhibition of FKBP2 expression increased proinsulin turnover with reduced intracellular proinsulin and insulin levels. This phenotype was accompanied by an increased proinsulin secretion and the formation of proinsulin high-molecular-weight complexes, a sign of proinsulin misfolding. FKBP2 knockout in pancreatic β-cells increased apoptosis without detectable up-regulation of ER stress response genes. Interestingly, FKBP2 mRNA was overexpressed in β-cells from pancreatic islets of T2D patients. Based on molecular modeling and an in vitro enzymatic assay, we suggest that proline at position 28 of the proinsulin B-chain (P28) is the substrate of FKBP2’s isomerization activity. We propose that this isomerization step catalyzed by FKBP2 is an essential sequence required for correct proinsulin folding. |
format | Online Article Text |
id | pubmed-9855983 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98559832023-01-21 FK506-Binding Protein 2 Participates in Proinsulin Folding Hoefner, Carolin Bryde, Tenna Holgersen Pihl, Celina Tiedemann, Sylvia Naiga Bresson, Sophie Emilie Hotiana, Hajira Ahmed Khilji, Muhammad Saad Santos, Theodore Dos Puglia, Michele Pisano, Paola Majewska, Mariola Durzynska, Julia Klindt, Kristian Klusek, Justyna Perone, Marcelo J. Bucki, Robert Hägglund, Per Mårten Gourdon, Pontus Emanuel Gotfryd, Kamil Urbaniak, Edyta Borowiak, Malgorzata Wierer, Michael MacDonald, Patrick Edward Mandrup-Poulsen, Thomas Marzec, Michal Tomasz Biomolecules Article Apart from chaperoning, disulfide bond formation, and downstream processing, the molecular sequence of proinsulin folding is not completely understood. Proinsulin requires proline isomerization for correct folding. Since FK506-binding protein 2 (FKBP2) is an ER-resident proline isomerase, we hypothesized that FKBP2 contributes to proinsulin folding. We found that FKBP2 co-immunoprecipitated with proinsulin and its chaperone GRP94 and that inhibition of FKBP2 expression increased proinsulin turnover with reduced intracellular proinsulin and insulin levels. This phenotype was accompanied by an increased proinsulin secretion and the formation of proinsulin high-molecular-weight complexes, a sign of proinsulin misfolding. FKBP2 knockout in pancreatic β-cells increased apoptosis without detectable up-regulation of ER stress response genes. Interestingly, FKBP2 mRNA was overexpressed in β-cells from pancreatic islets of T2D patients. Based on molecular modeling and an in vitro enzymatic assay, we suggest that proline at position 28 of the proinsulin B-chain (P28) is the substrate of FKBP2’s isomerization activity. We propose that this isomerization step catalyzed by FKBP2 is an essential sequence required for correct proinsulin folding. MDPI 2023-01-11 /pmc/articles/PMC9855983/ /pubmed/36671537 http://dx.doi.org/10.3390/biom13010152 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hoefner, Carolin Bryde, Tenna Holgersen Pihl, Celina Tiedemann, Sylvia Naiga Bresson, Sophie Emilie Hotiana, Hajira Ahmed Khilji, Muhammad Saad Santos, Theodore Dos Puglia, Michele Pisano, Paola Majewska, Mariola Durzynska, Julia Klindt, Kristian Klusek, Justyna Perone, Marcelo J. Bucki, Robert Hägglund, Per Mårten Gourdon, Pontus Emanuel Gotfryd, Kamil Urbaniak, Edyta Borowiak, Malgorzata Wierer, Michael MacDonald, Patrick Edward Mandrup-Poulsen, Thomas Marzec, Michal Tomasz FK506-Binding Protein 2 Participates in Proinsulin Folding |
title | FK506-Binding Protein 2 Participates in Proinsulin Folding |
title_full | FK506-Binding Protein 2 Participates in Proinsulin Folding |
title_fullStr | FK506-Binding Protein 2 Participates in Proinsulin Folding |
title_full_unstemmed | FK506-Binding Protein 2 Participates in Proinsulin Folding |
title_short | FK506-Binding Protein 2 Participates in Proinsulin Folding |
title_sort | fk506-binding protein 2 participates in proinsulin folding |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9855983/ https://www.ncbi.nlm.nih.gov/pubmed/36671537 http://dx.doi.org/10.3390/biom13010152 |
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