1sf1
NMR STRUCTURE OF HUMAN INSULIN under Amyloidogenic Condition, 15 STRUCTURES
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OverviewOverview
Insulin undergoes aggregation-coupled misfolding to form a cross-beta, assembly. Such fibrillation has long complicated its manufacture and use, in the therapy of diabetes mellitus. Of interest as a model for, disease-associated amyloids, insulin fibrillation is proposed to occur via, partial unfolding of a monomeric intermediate. Here, we describe the, solution structure of human insulin under amyloidogenic conditions (pH 2.4, and 60 degrees C). Use of an enhanced sensitivity cryogenic probe at high, magnetic field avoids onset of fibrillation during spectral acquisition. A, novel partial fold is observed in which the N-terminal segments of the A-, and B-chains detach from the core. Unfolding of the N-terminal alpha-helix, of the A-chain exposes a hydrophobic surface formed by native-like packing, of the remaining alpha-helices. The C-terminal segment of the B-chain, although not well ordered, remains tethered to this partial helical core., We propose that detachment of N-terminal segments makes possible aberrant, protein-protein interactions in an amyloidogenic nucleus. Non-cooperative, unfolding of the N-terminal A-chain alpha-helix resembles that observed in, models of proinsulin folding intermediates and foreshadows the extensive, alpha --> beta transition characteristic of mature fibrils.
DiseaseDisease
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]
About this StructureAbout this Structure
1SF1 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Mechanism of insulin fibrillation: the structure of insulin under amyloidogenic conditions resembles a protein-folding intermediate., Hua QX, Weiss MA, J Biol Chem. 2004 May 14;279(20):21449-60. Epub 2004 Feb 26. PMID:14988398
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