Distinct states of proinsulin misfolding in MIDY
dc.contributor.author | Haataja, Leena | |
dc.contributor.author | Arunagiri, Anoop | |
dc.contributor.author | Hassan, Anis | |
dc.contributor.author | Regan, Kaitlin | |
dc.contributor.author | Tsai, Billy | |
dc.contributor.author | Dhayalan, Balamurugan | |
dc.contributor.author | Weiss, Michael A. | |
dc.contributor.author | Liu, Ming | |
dc.contributor.author | Arvan, Peter | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | en_US |
dc.date.accessioned | 2023-02-23T19:08:47Z | |
dc.date.available | 2023-02-23T19:08:47Z | |
dc.date.issued | 2021-08 | |
dc.description.abstract | A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)-Cys(A20) "interchain" disulfide bond, facilitating formation of the Cys(B7)-Cys(A7) bridge. The third proinsulin disulfide, Cys(A6)-Cys(A11), is not required for anterograde trafficking, i.e., a "lose-A6/A11" mutant [Cys(A6), Cys(A11) both converted to Ser] is well secreted. Nevertheless, an unpaired Cys(A11) can participate in disulfide mispairings, causing ER retention of proinsulin. Among the many missense mutations causing the syndrome of Mutant INS gene-induced Diabetes of Youth (MIDY), all seem to exhibit perturbed proinsulin disulfide bond formation. Here, we have examined a series of seven MIDY mutants [including G(B8)V, Y(B26)C, L(A16)P, H(B5)D, V(B18)A, R(Cpep + 2)C, E(A4)K], six of which are essentially completely blocked in export from the ER in pancreatic β-cells. Three of these mutants, however, must disrupt the Cys(A6)-Cys(A11) pairing to expose a critical unpaired cysteine thiol perturbation of proinsulin folding and ER export, because when introduced into the proinsulin lose-A6/A11 background, these mutants exhibit native-like disulfide bonding and improved trafficking. This maneuver also ameliorates dominant-negative blockade of export of co-expressed wild-type proinsulin. A growing molecular understanding of proinsulin misfolding may permit allele-specific pharmacological targeting for some MIDY mutants. | en_US |
dc.eprint.version | Final published version | en_US |
dc.identifier.citation | Haataja L, Arunagiri A, Hassan A, et al. Distinct states of proinsulin misfolding in MIDY. Cell Mol Life Sci. 2021;78(16):6017-6031. doi:10.1007/s00018-021-03871-1 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/31438 | |
dc.language.iso | en_US | en_US |
dc.publisher | Springer | en_US |
dc.relation.isversionof | 10.1007/s00018-021-03871-1 | en_US |
dc.relation.journal | Cellular and Molecular Life Sciences | en_US |
dc.rights | Attribution 4.0 International | * |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | * |
dc.source | PMC | en_US |
dc.subject | Endoplasmic reticulum | en_US |
dc.subject | Disulfide bonds | en_US |
dc.subject | Protein trafficking | en_US |
dc.subject | Insulin | en_US |
dc.subject | Diabetes | en_US |
dc.title | Distinct states of proinsulin misfolding in MIDY | en_US |
dc.type | Article | en_US |