FK506-Binding Protein 2 Participates in Proinsulin Folding.

Autor:	Hoefner C; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark., Bryde TH; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark., Pihl C; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark., Tiedemann SN; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.; SAXOCON A/S, 2830 Virum, Denmark., Bresson SE; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway., Hotiana HA; Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark., Khilji MS; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.; Department of Biology, Linderstrøm-Lang Center for Protein Science, University of Copenhagen, 2200 Copenhagen, Denmark.; Department of Physiology, University of Veterinary and Animal Sciences, Lahore 54000, Punjab, Pakistan., Santos TD; Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada., Puglia M; Proteomics Research Infrastructure, University of Copenhagen, 2200 Copenhagen, Denmark., Pisano P; Proteomics Research Infrastructure, University of Copenhagen, 2200 Copenhagen, Denmark., Majewska M; Department of Genetics, Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, 61-712 Poznań, Poland., Durzynska J; Department of Genetics, Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, 61-712 Poznań, Poland., Klindt K; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark., Klusek J; Laboratory of Medical Genetics, Department of Surgical Medicine, Collegium Medicum, Jan Kochanowski University, 25-406 Kielce, Poland., Perone MJ; Immuno-Endocrinology, Diabetes & Metabolism Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET-Universidad Austral, Buenos Aires B1629AHJ, Argentina., Bucki R; Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, 15-089 Białystok, Poland., Hägglund PM; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark., Gourdon PE; Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark., Gotfryd K; Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark., Urbaniak E; Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, 61-712 Poznań, Poland., Borowiak M; Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, 61-712 Poznań, Poland., Wierer M; Proteomics Research Infrastructure, University of Copenhagen, 2200 Copenhagen, Denmark., MacDonald PE; Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada., Mandrup-Poulsen T; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark., Marzec MT; Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.; Institute of Health Sciences, Collegium Medicum, Jan Kochanowski University, 25-406 Kielce, Poland.
Jazyk:	angličtina
Zdroj:	Biomolecules [Biomolecules] 2023 Jan 11; Vol. 13 (1). Date of Electronic Publication: 2023 Jan 11.
DOI:	10.3390/biom13010152
Abstrakt:	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.
Databáze:	MEDLINE
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