Deciphering a Molecular Mechanism of Neonatal Diabetes Mellitus by the Chemical Synthesis of a Protein Diastereomer, [d-AlaB8]Human Proinsulin

Avital-Shmilovici, Michal; Whittaker, Jonathan; Weiss, Michael A.; Kent, Stephen B. H.

doi:10.1074/jbc.m114.572040

Cited by 19 publications

(21 citation statements)

References 55 publications

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“…As noted above, the folding pathway of proinsulin in the ER may be impacted adversely by an unfavorable ER folding environment. It has been recently shown that chemically synthetic proinsulin can robustly refold in vitro at pH 10; under these conditions the folding of some MIDY mutants can be accomplished successfully (Avital-Shmilovici et al, 2014). However, under condition of physiological pH within the ER, the folding environment seems to be less favorable for proinsulin folding.…”

Section: Proinsulin Misfolding In the Ermentioning

confidence: 99%

Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes☆

Sun

Cui

et al. 2015

Molecular Aspects of Medicine

162

117

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To maintain copious insulin granule stores in the face of ongoing metabolic demand, pancreatic beta cells must produce large quantities of proinsulin, the insulin precursor. Proinsulin biosynthesis can account for up to 30–50% of total cellular protein synthesis of beta cells. This puts pressure on the beta cell secretory pathway, especially the endoplasmic reticulum (ER), where proinsulin undergoes its initial folding, including the formation of three evolutionarily conserved disulfide bonds. In normal beta cells, up to 20% of newly synthesized proinsulin may fail to reach its native conformation, suggesting that proinsulin is a misfolding-prone protein. Misfolded proinsulin molecules can either be refolded to their native structure or degraded through ER associated degradation (ERAD) and autophagy. These degraded molecules decrease proinsulin yield but do not otherwise compromise beta cell function. However, under certain pathological conditions, proinsulin misfolding increases, exceeding the genetically-determined threshold of beta cells to handle the misfolded protein load. This results in accumulation of misfolded proinsulin in the ER – a causal factor leading to beta cell failure and diabetes. In patients with Mutant INS-gene induced diabetes of Youth (MIDY), increased proinsulin misfolding due to insulin gene mutations is the primary defect operating as a “first hit” to beta cells. Additionally, increased proinsulin misfolding can be secondary to an unfavorable ER folding environment due to genetic and/or environmental factors. Under these conditions, increased wild-type proinsulin misfolding becomes a “second hit” to the ER and beta cells, aggravating beta cell failure and diabetes. In this article, we describe our current understanding of the normal proinsulin folding pathway in the ER, and then review existing links between proinsulin misfolding, ER dysfunction, and beta cell failure in the development and progression of type 2, type 1, and some monogenic forms of diabetes.

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Section: Proinsulin Misfolding In the Ermentioning

confidence: 99%

Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes☆

Sun

Cui

et al. 2015

Molecular Aspects of Medicine

162

117

View full text Add to dashboard Cite

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“…Both teams utilized multi‐step conventional fragment condensation in constructing the linear precursor. More recently, this target was revisited by Kent and co‐workers who utilized their native ligation methodology to achieve an overall yield of 26%, based on the starting fragment .…”

Section: The Chemical Synthesis Of Proinsulin Igf‐i and Igf‐iimentioning

confidence: 99%

Chemical synthesis of peptides within the insulin superfamily

Liu

Zaykov

Levy

et al. 2016

Journal of Peptide Science

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The synthesis of insulin has inspired fundamental advances in the art of peptide science while simultaneously revealing the structure-function relationship of this centrally important metabolic hormone. This review highlights milestones in the chemical synthesis of insulin that can be divided into two separate approaches: (i) disulfide bond formation driven by protein folding and (ii) chemical reactivity-directed sequential disulfide bond formation. Common to the two approaches are the persistent challenges presented by the hydrophobic nature of the individual A-chain and B-chain and the need for selective disulfide formation under mildly oxidative conditions. The extension and elaboration of these synthetic approaches have been ongoing within the broader insulin superfamily. These structurally similar peptides include the insulin-like growth factors and also the related peptides such as relaxin that signal through G-protein-coupled receptors. After a half-century of advances in insulin chemistry, we have reached a point where synthesis is no longer limiting structural and biological investigation within this family of peptide hormones. The future will increasingly focus on the refinement of structure to meet medicinal purposes that have long been pursued, such as the development of a glucose-sensitive insulin. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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“…Chiral inversion even has been found to stabilize tertiary structural elements in certain cases 47 – 49 . In an interesting biomedically relevant case, D-substitution strategies applied to insulin have revealed that it undergoes conformational changes upon receptor binding 47 , an observation of relevance with respect to the molecular mechanisms of neonatal diabetes mellitus 50 . The chiral substitution strategy has also been previously applied to advantage in studying smaller peptides.…”

Section: Altering Backbone Conformational Landscapes With D-amino Acimentioning

confidence: 99%

Using chirality to probe the conformational dynamics and assembly of intrinsically disordered amyloid proteins

Raskatov

Teplow

2017

Sci Rep

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Intrinsically disordered protein (IDP) conformers occupy large regions of conformational space and display relatively flat energy surfaces. Amyloid-forming IDPs, unlike natively folded proteins, have folding trajectories that frequently involve movements up shallow energy gradients prior to the “downhill” folding leading to fibril formation. We suggest that structural perturbations caused by chiral inversions of amino acid side-chains may be especially valuable in elucidating these pathways of IDP folding. Chiral inversions are subtle in that they do not change side-chain size, flexibility, hydropathy, charge, or polarizability. They allow focus to be placed solely on the question of how changes in amino acid side-chain orientation, and the resultant alterations in peptide backbone structure, affect a peptide’s conformational landscape (Ramachandran space). If specific inversions affect folding and assembly, then the sites involved likely are important in mediating these processes. We suggest here a “focused chiral mutant library” approach for the unbiased study of amyloid-forming IDPs.

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Deciphering a Molecular Mechanism of Neonatal Diabetes Mellitus by the Chemical Synthesis of a Protein Diastereomer, [d-AlaB8]Human Proinsulin

Cited by 19 publications

References 55 publications

Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes☆

Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes☆

Chemical synthesis of peptides within the insulin superfamily

Using chirality to probe the conformational dynamics and assembly of intrinsically disordered amyloid proteins

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