Distinct states of proinsulin misfolding in MIDY

dc.contributor.authorHaataja, Leena
dc.contributor.authorArunagiri, Anoop
dc.contributor.authorHassan, Anis
dc.contributor.authorRegan, Kaitlin
dc.contributor.authorTsai, Billy
dc.contributor.authorDhayalan, Balamurugan
dc.contributor.authorWeiss, Michael A.
dc.contributor.authorLiu, Ming
dc.contributor.authorArvan, Peter
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicineen_US
dc.date.accessioned2023-02-23T19:08:47Z
dc.date.available2023-02-23T19:08:47Z
dc.date.issued2021-08
dc.description.abstractA 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.versionFinal published versionen_US
dc.identifier.citationHaataja 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/s00018-021-03871-1en_US
dc.identifier.urihttps://hdl.handle.net/1805/31438
dc.language.isoen_USen_US
dc.publisherSpringeren_US
dc.relation.isversionof10.1007/s00018-021-03871-1en_US
dc.relation.journalCellular and Molecular Life Sciencesen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0*
dc.sourcePMCen_US
dc.subjectEndoplasmic reticulumen_US
dc.subjectDisulfide bondsen_US
dc.subjectProtein traffickingen_US
dc.subjectInsulinen_US
dc.subjectDiabetesen_US
dc.titleDistinct states of proinsulin misfolding in MIDYen_US
dc.typeArticleen_US
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