ArticleThe Journal of biological chemistry2010
Deciphering the hidden informational content of protein sequences: foldability of proinsulin hinges on a flexible arm that is dispensable in the mature hormone.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- Exploring proinsulin proteostasis: insights into beta cell health and diabetes.Frontiers in molecular biosciences · 2025Review
- Regulated processing and secretion of a peptide precursor in cilia.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Structural Lessons From the Mutant Proinsulin Syndrome.Frontiers in endocrinology · 2021Review
- Evolution of insulin at the edge of foldability and its medical implications.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production.Cells · 2020Review
- "Register-shift" insulin analogs uncover constraints of proteotoxicity in protein evolution.The Journal of biological chemistry · 2020Article
- Biosynthesis, structure, and folding of the insulin precursor protein.Diabetes, obesity & metabolism · 2018Review
- Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes.Molecular aspects of medicine · 2015Review
- INS-gene mutations: from genetics and beta cell biology to clinical disease.Molecular aspects of medicine · 2015Review
- Diabetes mellitus due to the toxic misfolding of proinsulin variants.FEBS letters · 2013Review
- Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes.Diabetes · 2012Article
- The stability of myocilin olfactomedin domain variants provides new insight into glaucoma as a protein misfolding disorder.Biochemistry · 2011Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Protein sequences encode both structure and foldability. Whereas the interrelationship of sequence and structure has been extensively investigated, the origins of folding efficiency are enigmatic. We demonstrate that the folding of proinsulin requires a flexible N-terminal hydrophobic residue that is dispensable for the structure, activity, and stability of the mature hormone. This residue (Phe(B1) in placental mammals) is variably positioned within crystal structures and exhibits (1)H NMR motional narrowing in solution. Despite such flexibility, its deletion impaired insulin chain combination and led in cell culture to formation of non-native disulfide isomers with impaired secretion of the variant proinsulin. Cellular folding and secretion were maintained by hydrophobic substitutions at B1 but markedly perturbed by polar or charged side chains. We propose that, during folding, a hydrophobic side chain at B1 anchors transient long-range interactions by a flexible N-terminal arm (residues B1-B8) to mediate kinetic or thermodynamic partitioning among disulfide intermediates. Evidence for the overall contribution of the arm to folding was obtained by alanine scanning mutagenesis. Together, our findings demonstrate that efficient folding of proinsulin requires N-terminal sequences that are dispensable in the native state. Such arm-dependent folding can be abrogated by mutations associated with β-cell dysfunction and neonatal diabetes mellitus.
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