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

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 lambda 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 it 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.

SUBMITTER: Roberts AN

PROVIDER: S-EPMC298561 | biostudies-other | 1989 Dec

REPOSITORIES: biostudies-other

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

Roberts A N AN Leighton B B Todd J A JA Cockburn D D Schofield P N PN Sutton R R Holt S S Boyd Y Y Day A J AJ Foot E A EA

Proceedings of the National Academy of Sciences of the United States of America 19891201 24

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 lambda 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 ...[more]

PMID: 2690069

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Project description:Protein expression profiles in rat corporal smooth muscle tissue were compared between animal models of streptozotocin-induced diabetes mellitus (STZ-DM) and age-matched controls (AMCs) at 1 week and 2 months after induction of hyperglycemia with STZ treatment. At each time point, protein samples from four STZ-DM and four AMC rat corpora tissues were prepared independently and analyzed together across multiple quantitative two-dimensional gels using a pooled internal standard sample to quantify expression changes with statistical confidence. A total of 170 spots were differential expressed among the four experimental groups. A subsequent mass spectrometry analysis of the 170 spots identified a total of 57 unique proteins. Network analysis of these proteins using MetaCore suggested altered activity of transcriptional factors that are of too low abundance to be detected by the two-dimensional gel method. The proteins that were down-regulated with diabetes include isoforms of collagen that are precursors to fibril-forming collagen type 1; Hsp47, which assists and mediates the proper folding of procollagen; and several proteins whose abundance is controlled by sex hormones (e.g. CRP1 and A2U). On the other hand, proteins seen or predicted to be up-regulated include proteins involved in cell apoptosis (e.g. p53, 14-3-3-gamma, Serpinf1, Cct4, Cct5, and Sepina3n), proteins that neutralize the biological activity of nerve growth factor (e.g. anti-NGF 30), and proteins involved in lipid metabolism (e.g. apoA-I and apoA-IV). Subsequent Western blot validation analysis of p53, 14-3-3-gamma, and Hsp47 confirmed increased p53 and 14-3-3-gamma and decreased Hsp47 levels in separate samples. According to the results from the Western blot analysis, Hsp47 protein showed a approximately 3-fold decrease at 1 week and was virtually undetectable at 2 months in diabetic versus control. Taken together, our results identify novel candidate proteins playing a role in erectile dysfunction in diabetes resulting from STZ treatment.

Project description:BackgroundMultiple functional genomics data for complex human diseases have been published and made available by researchers worldwide. The main goal of these studies is the detailed analysis of a particular aspect of the disease. Complementary, meta-analysis approaches try to extract supersets of disease genes and interaction networks by integrating and combining these individual studies using statistical approaches.ResultsHere we report on a meta-analysis approach that integrates data of heterogeneous origin in the domain of type-2 diabetes mellitus (T2DM). Different data sources such as DNA microarrays and, complementing, qualitative data covering several human and mouse tissues are integrated and analyzed with a Bootstrap scoring approach in order to extract disease relevance of the genes. The purpose of the meta-analysis is two-fold: on the one hand it identifies a group of genes with overall disease relevance indicating common, tissue-independent processes related to the disease; on the other hand it identifies genes showing specific alterations with respect to a single study. Using a random sampling approach we computed a core set of 213 T2DM genes across multiple tissues in human and mouse, including well-known genes such as Pdk4, Adipoq, Scd, Pik3r1, Socs2 that monitor important hallmarks of T2DM, for example the strong relationship between obesity and insulin resistance, as well as a large fraction (128) of yet barely characterized novel candidate genes. Furthermore, we explored functional information and identified cellular networks associated with this core set of genes such as pathway information, protein-protein interactions and gene regulatory networks. Additionally, we set up a web interface in order to allow users to screen T2DM relevance for any - yet non-associated - gene.ConclusionIn our paper we have identified a core set of 213 T2DM candidate genes by a meta-analysis of existing data sources. We have explored the relation of these genes to disease relevant information and - using enrichment analysis - we have identified biological networks on different layers of cellular information such as signaling and metabolic pathways, gene regulatory networks and protein-protein interactions. The web interface is accessible via http://t2dm-geneminer.molgen.mpg.de.

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

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

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