TY - JOUR

T1 - FK506-Binding Protein 2 Participates in Proinsulin Folding

AU - Hoefner, Carolin

AU - Bryde, Tenna Holgersen

AU - Pihl, Celina

AU - Tiedemann, Sylvia Naiga

AU - Bresson, Sophie Emilie

AU - Hotiana, Hajira Ahmed

AU - Khilji, Muhammad Saad

AU - Santos, Theodore Dos

AU - Puglia, Michele

AU - Pisano, Paola

AU - Majewska, Mariola

AU - Durzynska, Julia

AU - Klindt, Kristian

AU - Klusek, Justyna

AU - Perone, Marcelo J.

AU - Bucki, Robert

AU - Hägglund, Per Mårten

AU - Gourdon, Pontus Emanuel

AU - Gotfryd, Kamil

AU - Urbaniak, Edyta

AU - Borowiak, Malgorzata

AU - Wierer, Michael

AU - MacDonald, Patrick Edward

AU - Mandrup-Poulsen, Thomas

AU - Marzec, Michal Tomasz

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.3390/biom13010152

DO - 10.3390/biom13010152

M3 - Journal article

C2 - 36671537

VL - 13

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 1

M1 - 152

ER -