Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide.
Aggregation of Islet Amyloid Polypeptide (IAPP) has been implicated in the development of type II diabetes. Because IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers causes disruption of the cellular membrane and is responsible for the death of beta-cells during type II diabetes. Previous studies have shown that the N-terminal 1-19 region, rather than the amyloidogenic 20-29 region, is primarily responsible for the interaction of the IAPP peptide with membranes. Liposome leakage experiments presented in this study confirm that the pathological membrane disrupting activity of the full-length hIAPP is also shared by hIAPP 1-19. The hIAPP 1-19 fragment at a low concentration of peptide induces membrane disruption to a near identical extent as the full-length peptide. At higher peptide concentrations, the hIAPP 1-19 fragment induces a greater extent of membrane disruption than the full-length peptide. Similar to the full-length peptide, hIAPP 1-19 exhibits a random coil conformation in solution and adopts an alpha-helical conformation upon binding to lipid membranes. However, unlike the full-length peptide, the hIAPP 1-19 fragment did not form amyloid fibers when incubated with POPG vesicles. These results indicate that membrane disruption can occur independently from amyloid formation in IAPP, and the sequences responsible for amyloid formation and membrane disruption are located in different regions of the peptide.
Brender
Jeffrey R
JR
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Lee
Edgar L
EL
Cavitt
Marchello A
MA
Gafni
Ari
A
Steel
Duncan G
DG
Ramamoorthy
Ayyalusamy
A
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005452:Fluoresceins / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D058228:Islet Amyloid Polypeptide; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000737:chemistry*
D000682:Amyloid; D005452:Fluoresceins; D005456:Fluorescent Dyes; C521761:IAPP(20-29) peptide; D058228:Islet Amyloid Polypeptide; D008081:Liposomes; D010446:Peptide Fragments; D010715:Phosphatidylglycerols; C024098:6-carboxyfluorescein; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol