Distinct states of proinsulin misfolding in MIDY.
Diabetes
Disulfide bonds
Endoplasmic reticulum
Insulin
Protein trafficking
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
received:
09
02
2021
accepted:
01
06
2021
revised:
17
05
2021
pubmed:
11
7
2021
medline:
3
8
2021
entrez:
10
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34245311
doi: 10.1007/s00018-021-03871-1
pii: 10.1007/s00018-021-03871-1
pmc: PMC8316239
doi:
Substances chimiques
Disulfides
0
Insulin
0
Proinsulin
9035-68-1
Cysteine
K848JZ4886
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6017-6031Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK111174
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK040949
Pays : United States
Organisme : National Natural Science Foundation of China
ID : 81830025
Organisme : National Natural Science Foundation of China
ID : 81620108004
Organisme : NIDDK NIH HHS
ID : R01 DK048280
Pays : United States
Organisme : National Key Clinical Specialty Discipline Construction Program of China
ID : 2019YFA0802502
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK48280
Pays : United States
Informations de copyright
© 2021. The Author(s).
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