Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus

A. N. Roberts, B. Leighton, J. A. Todd, D. Cockburn, P. N. Schofield, R. Sutton, S. Holt, Y. Boyd, A. J. Day, E. A. Foot, A. C. Willis, K. B M Reid, G. J S Cooper

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The 37-amino acid peptide called amylin is a major component of the islet amyloid deposited in the pancreases of persons with type 2 diabetes mellitus. We report the isolation of a partial cDNA clone and a phage λ genomic clone of the coding region of the amylin gene. The DNA sequence encodes a protein sequence identical to that of amylin isolated from the amyloid found in the diabetic pancreas and shows that amylin is likely to be synthesized as a precursor peptide, now named proamylin. We have demonstrated that the amylin gene is present on chromosome 12 and that is probably transcribed in the islets of Langerhans. The sequences of the genes for amylin and the calcitonin gene-related peptides (CGRPs) show strong similarity, especially over their 5' coding regions, where both peptides have a conserved intramolecular disulfide bridge, and also over their 3' coding regions, where the presence of a glycine codon strongly suggests that the carboxyl-terminal residue of amylin, like that of CGRP, is amidated. To examine the functional relevance of these posttranslational modifications, the biological activity of amylin synthesized with or without the disulfide bridge and /or amidation was measured. It was found that both features are necessary for full biological activity, thereby confirming the functional importance of those regions of the molecule whose sequences are conserved at both protein and genetic levels.
    Original languageEnglish
    Pages (from-to)9662-9666
    Number of pages4
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume86
    Issue number24
    DOIs
    Publication statusPublished - 1989

    Keywords

    • carboxyl-terminal amidation
    • chromosome 12
    • Genomic clone
    • glycogen synthesis
    • insulin resistance

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