Islet amyloid polypeptide (IAPP): cDNA cloning and identification of an amyloidogenic region associated with the species-specific occurrence of age-related diabetes mellitus

• Published in: Experimental cell research Vol. 183; no. 2; pp. 484 - 493
• Main Authors: Betsholtz, Christer, Svensson, Viveka, Rorsman, Fredrik, Engström, Ulla, Westermark, Gunilla T., Wilander, Erik, Johnson, Kenneth, Westermark, Per
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.1989
• Subjects: 550301 - Cytology- Tracer Techniques; age; AMINO ACID SEQUENCE; AMYLASE; amyloid; Amyloid - genetics; ANIMALS; Base Sequence; BASIC BIOLOGICAL SCIENCES; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; BIOLOGICAL EVOLUTION; BODY; Calcitonin - genetics; Calcitonin Gene-Related Peptide; CATS; cloning; Cloning, Molecular; DAYS LIVING RADIOISOTOPES; diabetes; DIABETES MELLITUS; Diabetes Mellitus, Type 2 - genetics; DIGESTIVE SYSTEM; DISEASES; DNA; DNA - genetics; DNA - isolation & purification; DNA SEQUENCING; DOGS; ENDOCRINE DISEASES; ENDOCRINE GLANDS; ENZYMES; Gene Amplification; Genes; GLANDS; GLYCOSYL HYDROLASES; GUINEA PIGS; Humans; HYDROLASES; Islet Amyloid Polypeptide; Islets of Langerhans - metabolism; ISOTOPES; LIGHT NUCLEI; MAMMALS; MAN; METABOLIC DISEASES; mice; Molecular Sequence Data; MOLECULAR STRUCTURE; Multigene Family; Neuropeptides - genetics; NUCLEI; NUCLEIC ACIDS; O-GLYCOSYL HYDROLASES; ODD-ODD NUCLEI; Oligonucleotide Probes; ORGANIC COMPOUNDS; ORGANS; PANCREAS; PATHOGENESIS; PEPTIDES; PHOSPHORUS 32; PHOSPHORUS ISOTOPES; POLYPEPTIDES; PRIMATES; Procyon lotor; PROTEINS; Raccoons; RADIOISOTOPES; rats; RECOMBINANT DNA; RODENTS; Sequence Homology, Nucleic Acid; STRUCTURAL CHEMICAL ANALYSIS; VERTEBRATES
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/0014-4827(89)90407-2

We have cloned and sequenced a human islet amyloid polypeptide (IAPP) cDNA. A secretory 89 amino acid IAPP protein precursor is predicted from which the 37 amino acid IAPP molecule is formed by amino- and carboxyterminal proteolytic processing. The IAPP peptide is 43–46% identical in amino acid sequence to the two members of the calcitonin gene-related peptide (CGRP) family. Evolutionary conserved proteolytic processing sites indicate that similar proteases are involved in the maturation of IAPP and CGRP and that the LAPP amyloid polypeptide is identical to the normal proteolytic product of the IAPP precursor. A synthetic peptide corresponding to a carboxyteminal fragment of human IAPP is shown to spontaneously form amyloid-like fibrils in vitro. Antibodies against this peptide cross-react with IAPP from species that develop amyloid in pancreatic islets in conjunction with age-related diabetes mellitus (human, cat, racoon), but do not cross-react with IAPP from other tested species (mouse, rat, guinea pig, dog). Thus, a species-specific structural motif in the putative amyloidogenic region of IAPP is associated with both amyloid formation and the development of age-related diabetes mellitus. This provides a new molecular clue to the pathogenesis of this disease.