BioChem - DOS

FK506-Binding Protein 2 Participates in Proinsulin Folding

Biomolecules

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; Hä gglund, Per Må rten; Gourdon, Pontus Emanuel; Gotfryd, Kamil; Urbaniak, Edyta; Borowiak, Malgorzata; Wierer, Michael; MacDonald, Patrick Edward; Mandrup-Poulsen, Thomas; Marzec, Michal Tomasz

<P>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 &beta;-cells increased apoptosis without detectable up-regulation of ER stress response genes. Interestingly, FKBP2 mRNA was overexpressed in &beta;-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&rsquo;s isomerization activity. We propose that this isomerization step catalyzed by FKBP2 is an essential sequence required for correct proinsulin folding.</P>

2023

MDPI

2218-273x

13

1

pp.152

10.3390/biom13010152

http://click.ndsl.kr/servlet/OpenAPIDetailView?keyValue=05787966&target=NART&cn=NART123156722

FKBP2; proinsulin; proline isomerization; endoplasmic reticulum