Browsing by Subject "Folding efficiency"

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    Diabetes mellitus due to the toxic misfolding of proinsulin variants
    (Elsevier, 2013) Weiss, Michael A.; Biochemistry and Molecular Biology, School of Medicine
    Dominant mutations in the human insulin gene can lead to pancreatic β-cell dysfunction and diabetes mellitus due to toxic folding of a mutant proinsulin. Analogous to a classical mouse model (the Akita mouse), this monogenic syndrome highlights the susceptibility of human β-cells to endoreticular stress due to protein misfolding and aberrant aggregation. The clinical mutations directly or indirectly perturb native disulfide pairing. Whereas the majority of mutations introduce or remove a cysteine (leading in either case to an unpaired residue), non-cysteine-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the evolution of insulin has been constrained not only by its structure and function, but also by the susceptibility of its single-chain precursor to impaired foldability.
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    Evolution of insulin at the edge of foldability and its medical implications
    (National Academy of Sciences, 2020-11-24) Rege, Nischay K.; Liu, Ming; Yang, Yanwu; Dhayalan, Balamurugan; Wickramasinghe, Nalinda P.; Chen, Yen-Shan; Rahimi, Leili; Guo, Huan; Haataja, Leena; Sun, Jinhong; Ismail-Beigi, Faramarz; Phillips, Nelson B.; Arvan, Peter; Weiss, Michael A.; Biochemistry and Molecular Biology, School of Medicine
    Proteins have evolved to be foldable, and yet determinants of foldability may be inapparent once the native state is reached. Insight has emerged from studies of diseases of protein misfolding, exemplified by monogenic diabetes mellitus due to mutations in proinsulin leading to endoplasmic reticulum stress and β-cell death. Cellular foldability of human proinsulin requires an invariant Phe within a conserved crevice at the receptor-binding surface (position B24). Any substitution, even related aromatic residue TyrB24, impairs insulin biosynthesis and secretion. As a seeming paradox, a monomeric TyrB24 insulin analog exhibits a native-like structure in solution with only a modest decrement in stability. Packing of TyrB24 is similar to that of PheB24, adjoining core cystine B19-A20 to seal the core; the analog also exhibits native self-assembly. Although affinity for the insulin receptor is decreased ∼20-fold, biological activities in cells and rats were within the range of natural variation. Together, our findings suggest that the invariance of PheB24 among vertebrate insulins and insulin-like growth factors reflects an essential role in enabling efficient protein folding, trafficking, and secretion, a function that is inapparent in native structures. In particular, we envision that the para-hydroxyl group of TyrB24 hinders pairing of cystine B19-A20 in an obligatory on-pathway folding intermediate. The absence of genetic variation at B24 and other conserved sites near this disulfide bridge-excluded due to β-cell dysfunction-suggests that insulin has evolved to the edge of foldability. Nonrobustness of a protein's fitness landscape underlies both a rare monogenic syndrome and "diabesity" as a pandemic disease of civilization.
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    Structural Lessons From the Mutant Proinsulin Syndrome
    (Frontiers Media, 2021-09-30) Dhayalan, Balamurugan; Chatterjee, Deepak; Chen, Yen-Shan; Weiss, Michael A.; Biochemistry and Molecular Biology, School of Medicine
    Insight into folding mechanisms of proinsulin has been provided by analysis of dominant diabetes-associated mutations in the human insulin gene (INS). Such mutations cause pancreatic β-cell dysfunction due to toxic misfolding of a mutant proinsulin and impairment in trans of wild-type insulin secretion. Anticipated by the “Akita” mouse (a classical model of monogenic diabetes mellitus; DM), this syndrome illustrates the paradigm endoreticulum (ER) stress leading to intracellular proteotoxicity. Diverse clinical mutations directly or indirectly perturb native disulfide pairing leading to protein misfolding and aberrant aggregation. Although most introduce or remove a cysteine (Cys; leading in either case to an unpaired thiol group), non-Cys-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the hormone’s evolution has been constrained not only by structure-function relationships, but also by the susceptibility of its single-chain precursor to impaired foldability. An intriguing hypothesis posits that INS overexpression in response to peripheral insulin resistance likewise leads to chronic ER stress and β-cell dysfunction in the natural history of non-syndromic Type 2 DM. Cryptic contributions of conserved residues to folding efficiency, as uncovered by rare genetic variants, define molecular links between biophysical principles and the emerging paradigm of Darwinian medicine: Biosynthesis of proinsulin at the edge of non-foldability provides a key determinant of “diabesity” as a pandemic disease of civilization.