Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Distinct states of proinsulin misfolding in MIDY 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 {beta}-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.
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The categories of this paper are: cognition
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The categories of this paper are: physiology
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The categories of this paper are: systems
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The categories of this paper are: zoology
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The categories of this paper are: genetics
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The categories of this paper are: evolutionary
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The categories of this paper are: behavior
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The categories of this paper are: developmental
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The categories of this paper are: ecology
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The categories of this paper are: molecular
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The categories of this paper are: animal
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The categories of this paper are: immunology
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The categories of this paper are: pathology
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The categories of this paper are: genomics
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The categories of this paper are: pharmacology
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The categories of this paper are: bioengineering