Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation.
Islet amyloid polypeptide (IAPP), a putative polypeptide hormone, is a product of pancreatic beta-cells and the major constituent of the amyloid deposits seen mainly in islets of type 2 diabetic humans and diabetic cats. The connection between IAPP amyloid formation and diabetes is unknown, but a limited segment of the IAPP molecule, positions 20-29, seems responsible for the aggregation to fibrils. Differences in the amino acid sequence of this region probably determine whether or not islet amyloid can develop in a particular species. Amyloid fibril formation can be mimicked in vitro with the aid of synthetic peptides. With this technique we show that peptides corresponding to IAPP positions 20-29 of human and cat, species that develop IAPP-derived islet amyloid, form amyloid-like fibrils in vitro. The corresponding IAPP segment from three rodent species that do not develop IAPP-derived amyloid did not give rise to fibrils. Substitution of the human IAPP-(20-29) decapeptide with one or two amino acid residues from species without islet amyloid generally reduced the capacity to form fibrils. We conclude that the sequence Ala-Ile-Leu-Ser-Ser, corresponding to positions 25-29 of human IAPP, is strongly amyloidogenic and that a proline-for-serine substitution in position 28, as in several rodents, almost completely inhibits formation of amyloid fibrils.
Department of Pathology I, University Hospital, Linköping, Sweden.
P
P
Westermark
U
U
Engström
K H
KH
Johnson
G T
GT
Westermark
C
C
Betsholtz
D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics* / Q000502:physiology / Q000648:ultrastructure; D000686:Amyloidosis / Q000473:pathology*; D000818:Animals; D002415:Cats; D006224:Cricetinae; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000473:pathology; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D011498:Protein Precursors