R1526 residue in arginine/proinsulin binding domain of UGGT1 is involved in proinsulin binding

Abstract

Arginine releases proinsulin from binding to UGGT1 in the endoplasmic reticulum (ER). PSIPRED analysis showed that the arginine/proinsulin binding domain (A/PBD) in the C-terminal region of UGGT1 forms a disordered region, which is flexible and outside of the main protein structure. Both arginine and proinsulin may easily access the disordered region of A/PBD. Using the SNP library, two variants, Q1518∗ and R1526C, were identified in this region. UGGT1^Q1518∗ protein is a deficient form of A/PBD and ER-retention signal (ERRS). UGGT1^Q1518∗ protein in cell analysis reveals that mutated protein is mainly secreted from the cells because it lacks ERRS. We found another UGGT1 variant, UGGT1^R1526C. At the molecular level, less interaction of proinsulin with UGGT1 was observed in both human UGGT1^R1526C and mouse UGGT1^L1518C with/without arginine. However, UGGT1^R1526C and UGGT1^WT interact with arginine similarly. We identified several amino acid residues for the arginine and proinsulin interaction. Here, the R1526 residue of UGGT1 is involved in proinsulin-interaction and is not involved in arginine-interaction.

Keywords: Arginine; Disordered region; ER; Proinsulin; UGGT1.