FK506-Binding Protein 2 Participates in Proinsulin Folding

Autores
Hoefner, Carolin; Bryde, Tenna Holgersen; Pihl, Celina; Tiedemann, Sylvia Naiga; Bresson, Sophie Emilie; Hotiana, Hajira Ahmed; Khilji, Muhammad Saad; Dos Santos, Theodore; Puglia, Michele; Pisano, Paola; Majewska, Mariola; Durzynska, Julia; Klindt, Kristian; Klusek, Justyna; Perone, Marcelo Javier; 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
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Hoefner, Carolin. Universidad de Copenhagen; Dinamarca
Fil: Bryde, Tenna Holgersen. Universidad de Copenhagen; Dinamarca
Fil: Pihl, Celina. Universidad de Copenhagen; Dinamarca
Fil: Tiedemann, Sylvia Naiga. Universidad de Copenhagen; Dinamarca
Fil: Bresson, Sophie Emilie. Universidad de Copenhagen; Dinamarca
Fil: Hotiana, Hajira Ahmed. Universidad de Copenhagen; Dinamarca
Fil: Khilji, Muhammad Saad. Universidad de Copenhagen; Dinamarca
Fil: Dos Santos, Theodore. University of Alberta; Canadá
Fil: Puglia, Michele. Universidad de Copenhagen; Dinamarca
Fil: Pisano, Paola. Universidad de Copenhagen; Dinamarca
Fil: Majewska, Mariola. Adam Mickiewicz University; Polonia
Fil: Durzynska, Julia. Adam Mickiewicz University; Polonia
Fil: Klindt, Kristian. Universidad de Copenhagen; Dinamarca
Fil: Klusek, Justyna. No especifíca;
Fil: Perone, Marcelo Javier. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Bucki, Robert. Medical University of Białystok; Polonia
Fil: Hägglund, Per Mårten. Universidad de Copenhagen; Dinamarca
Fil: Gourdon, Pontus Emanuel. Universidad de Copenhagen; Dinamarca
Fil: Gotfryd, Kamil. Universidad de Copenhagen; Dinamarca
Fil: Urbaniak, Edyta. Adam Mickiewicz University, ; Polonia
Fil: Borowiak, Malgorzata. Adam Mickiewicz University, ; Polonia
Fil: Wierer, Michael. Universidad de Copenhagen; Dinamarca
Fil: MacDonald, Patrick Edward. University of Alberta; Canadá
Fil: Mandrup Poulsen, Thomas. Universidad de Copenhagen; Dinamarca
Fil: Marzec, Michal Tomasz. Universidad de Copenhagen; Dinamarca
Materia
ENDOPLASMIC RETICULUM
FKBP2
PROINSULIN
PROLINE ISOMERIZATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/235592
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/235592
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling FK506-Binding Protein 2 Participates in Proinsulin FoldingHoefner, CarolinBryde, Tenna HolgersenPihl, CelinaTiedemann, Sylvia NaigaBresson, Sophie EmilieHotiana, Hajira AhmedKhilji, Muhammad SaadDos Santos, TheodorePuglia, MichelePisano, PaolaMajewska, MariolaDurzynska, JuliaKlindt, KristianKlusek, JustynaPerone, Marcelo JavierBucki, RobertHägglund, Per MårtenGourdon, Pontus EmanuelGotfryd, KamilUrbaniak, EdytaBorowiak, MalgorzataWierer, MichaelMacDonald, Patrick EdwardMandrup Poulsen, ThomasMarzec, Michal TomaszENDOPLASMIC RETICULUMFKBP2PROINSULINPROLINE ISOMERIZATIONhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Apart 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.Fil: Hoefner, Carolin. Universidad de Copenhagen; DinamarcaFil: Bryde, Tenna Holgersen. Universidad de Copenhagen; DinamarcaFil: Pihl, Celina. Universidad de Copenhagen; DinamarcaFil: Tiedemann, Sylvia Naiga. Universidad de Copenhagen; DinamarcaFil: Bresson, Sophie Emilie. Universidad de Copenhagen; DinamarcaFil: Hotiana, Hajira Ahmed. Universidad de Copenhagen; DinamarcaFil: Khilji, Muhammad Saad. Universidad de Copenhagen; DinamarcaFil: Dos Santos, Theodore. University of Alberta; CanadáFil: Puglia, Michele. Universidad de Copenhagen; DinamarcaFil: Pisano, Paola. Universidad de Copenhagen; DinamarcaFil: Majewska, Mariola. Adam Mickiewicz University; PoloniaFil: Durzynska, Julia. Adam Mickiewicz University; PoloniaFil: Klindt, Kristian. Universidad de Copenhagen; DinamarcaFil: Klusek, Justyna. No especifíca;Fil: Perone, Marcelo Javier. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Bucki, Robert. Medical University of Białystok; PoloniaFil: Hägglund, Per Mårten. Universidad de Copenhagen; DinamarcaFil: Gourdon, Pontus Emanuel. Universidad de Copenhagen; DinamarcaFil: Gotfryd, Kamil. Universidad de Copenhagen; DinamarcaFil: Urbaniak, Edyta. Adam Mickiewicz University, ; PoloniaFil: Borowiak, Malgorzata. Adam Mickiewicz University, ; PoloniaFil: Wierer, Michael. Universidad de Copenhagen; DinamarcaFil: MacDonald, Patrick Edward. University of Alberta; CanadáFil: Mandrup Poulsen, Thomas. Universidad de Copenhagen; DinamarcaFil: Marzec, Michal Tomasz. Universidad de Copenhagen; DinamarcaMDPI2023-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/235592Hoefner, Carolin; Bryde, Tenna Holgersen; Pihl, Celina; Tiedemann, Sylvia Naiga; Bresson, Sophie Emilie; et al.; FK506-Binding Protein 2 Participates in Proinsulin Folding; MDPI; Biomolecules; 13; 1; 1-2023; 1-202218-273XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3390/biom13010152info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:38:14Zoai:ri.conicet.gov.ar:11336/235592instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:38:14.867CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv FK506-Binding Protein 2 Participates in Proinsulin Folding
title FK506-Binding Protein 2 Participates in Proinsulin Folding
spellingShingle FK506-Binding Protein 2 Participates in Proinsulin Folding
Hoefner, Carolin
ENDOPLASMIC RETICULUM
FKBP2
PROINSULIN
PROLINE ISOMERIZATION
title_short 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_sort FK506-Binding Protein 2 Participates in Proinsulin Folding
dc.creator.none.fl_str_mv Hoefner, Carolin
Bryde, Tenna Holgersen
Pihl, Celina
Tiedemann, Sylvia Naiga
Bresson, Sophie Emilie
Hotiana, Hajira Ahmed
Khilji, Muhammad Saad
Dos Santos, Theodore
Puglia, Michele
Pisano, Paola
Majewska, Mariola
Durzynska, Julia
Klindt, Kristian
Klusek, Justyna
Perone, Marcelo Javier
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 Hoefner, Carolin
author_facet Hoefner, Carolin
Bryde, Tenna Holgersen
Pihl, Celina
Tiedemann, Sylvia Naiga
Bresson, Sophie Emilie
Hotiana, Hajira Ahmed
Khilji, Muhammad Saad
Dos Santos, Theodore
Puglia, Michele
Pisano, Paola
Majewska, Mariola
Durzynska, Julia
Klindt, Kristian
Klusek, Justyna
Perone, Marcelo Javier
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_role author
author2 Bryde, Tenna Holgersen
Pihl, Celina
Tiedemann, Sylvia Naiga
Bresson, Sophie Emilie
Hotiana, Hajira Ahmed
Khilji, Muhammad Saad
Dos Santos, Theodore
Puglia, Michele
Pisano, Paola
Majewska, Mariola
Durzynska, Julia
Klindt, Kristian
Klusek, Justyna
Perone, Marcelo Javier
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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ENDOPLASMIC RETICULUM
FKBP2
PROINSULIN
PROLINE ISOMERIZATION
topic ENDOPLASMIC RETICULUM
FKBP2
PROINSULIN
PROLINE ISOMERIZATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Hoefner, Carolin. Universidad de Copenhagen; Dinamarca
Fil: Bryde, Tenna Holgersen. Universidad de Copenhagen; Dinamarca
Fil: Pihl, Celina. Universidad de Copenhagen; Dinamarca
Fil: Tiedemann, Sylvia Naiga. Universidad de Copenhagen; Dinamarca
Fil: Bresson, Sophie Emilie. Universidad de Copenhagen; Dinamarca
Fil: Hotiana, Hajira Ahmed. Universidad de Copenhagen; Dinamarca
Fil: Khilji, Muhammad Saad. Universidad de Copenhagen; Dinamarca
Fil: Dos Santos, Theodore. University of Alberta; Canadá
Fil: Puglia, Michele. Universidad de Copenhagen; Dinamarca
Fil: Pisano, Paola. Universidad de Copenhagen; Dinamarca
Fil: Majewska, Mariola. Adam Mickiewicz University; Polonia
Fil: Durzynska, Julia. Adam Mickiewicz University; Polonia
Fil: Klindt, Kristian. Universidad de Copenhagen; Dinamarca
Fil: Klusek, Justyna. No especifíca;
Fil: Perone, Marcelo Javier. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Bucki, Robert. Medical University of Białystok; Polonia
Fil: Hägglund, Per Mårten. Universidad de Copenhagen; Dinamarca
Fil: Gourdon, Pontus Emanuel. Universidad de Copenhagen; Dinamarca
Fil: Gotfryd, Kamil. Universidad de Copenhagen; Dinamarca
Fil: Urbaniak, Edyta. Adam Mickiewicz University, ; Polonia
Fil: Borowiak, Malgorzata. Adam Mickiewicz University, ; Polonia
Fil: Wierer, Michael. Universidad de Copenhagen; Dinamarca
Fil: MacDonald, Patrick Edward. University of Alberta; Canadá
Fil: Mandrup Poulsen, Thomas. Universidad de Copenhagen; Dinamarca
Fil: Marzec, Michal Tomasz. Universidad de Copenhagen; Dinamarca
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.
publishDate 2023
dc.date.none.fl_str_mv 2023-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/235592
Hoefner, Carolin; Bryde, Tenna Holgersen; Pihl, Celina; Tiedemann, Sylvia Naiga; Bresson, Sophie Emilie; et al.; FK506-Binding Protein 2 Participates in Proinsulin Folding; MDPI; Biomolecules; 13; 1; 1-2023; 1-20
2218-273X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/235592
identifier_str_mv Hoefner, Carolin; Bryde, Tenna Holgersen; Pihl, Celina; Tiedemann, Sylvia Naiga; Bresson, Sophie Emilie; et al.; FK506-Binding Protein 2 Participates in Proinsulin Folding; MDPI; Biomolecules; 13; 1; 1-2023; 1-20
2218-273X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3390/biom13010152
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846083501354385408
score 13.22299

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