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NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A2-ALA, HIS-B10-ASP, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

To investigate the cooperativity of insulin's structure, a cavity-forming, substitution was introduced within the hydrophobic core of an engineered, monomer. The substitution, Ile(A2)-->Ala in the A1-A8 alpha-helix, does, not impair disulfide pairing between chains. In accord with past studies, of cavity-forming mutations in globular proteins, a decrement was observed, in thermodynamic stability (DeltaDeltaG(u) 0.4-1.2 kcal/mole)., Unexpectedly, CD studies indicate an attenuated alpha-helix content, which, is assigned by NMR spectroscopy to selective destabilization of the A1-A8, segment. The analog's solution structure is otherwise similar to that of, native insulin, including the B chain's supersecondary structure and a, major portion of the hydrophobic core. Our results show that (1) a, cavity-forming mutation in a globular protein can lead to segmental, unfolding, (2) tertiary packing of Ile(A2), a residue of low helical, propensity, stabilizes the A1-A8 alpha-helix, and (3) folding of this, segment is not required for native disulfide pairing or overall structure., We discuss these results in relation to a hierarchical pathway of protein, folding and misfolding. The Ala(A2) analog's low biological activity (0.5%, relative to the parent monomer) highlights the importance of the A1-A8, alpha-helix in receptor recognition.

Disease

Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]

About this Structure

1K3M is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.

Reference

A cavity-forming mutation in insulin induces segmental unfolding of a surrounding alpha-helix., Xu B, Hua QX, Nakagawa SH, Jia W, Chu YC, Katsoyannis PG, Weiss MA, Protein Sci. 2002 Jan;11(1):104-16. PMID:11742127

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