| Structural analysis of proinsulin hexamer assembly by hydroxyl radical footprinting and computational modeling. | |
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MedLine Citation:
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PMID: 22033917 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Mutations in the insulin gene can impair proinsulin folding and cause diabetes mellitus. Although crystal structures of insulin dimers and hexamers are well established, proinsulin is refractory to crystallization. Whereas an NMR structure of an engineered proinsulin monomer has been reported, structures of the wild-type monomer and hexamer remain undetermined. We have utilized hydroxyl-radical footprinting and molecular modeling to characterize these structures. Differences between the footprints of insulin and proinsulin, defining a ″shadow″ of the connecting (C) domain, were employed to refine the model. Our results demonstrate that in its monomeric form (i) proinsulin contains a native-like insulin moiety and (ii) the C-domain footprint resides within an adjoining segment (residues B23-B29) that is accessible to modification in insulin but not proinsulin. Corresponding oxidation rates were observed within core insulin moieties of insulin- and proinsulin hexamers, suggesting that the proinsulin hexamer retains an A/B structure similar to that of insulin. Further similarities in rates of oxidation between the respective C domains of proinsulin monomers and hexamers suggest that this loop in each case flexibly projects from an outer surface. Although dimerization or hexamer assembly would not be impaired, an ensemble of predicted C-domain positions would block hexamer-hexamer stacking as visualized in classical crystal lattices. We anticipate that protein footprinting in combination with modeling, as illustrated here, will enable comparative studies of diabetes-associated mutant proinsulins and their aberrant modes of aggregation. |
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Authors:
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Janna G Kiselar; Manish Datt; Mark R Chance; Michael A Weiss |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-26 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Case Western Reserve University, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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