Polymorphic fibrillar assembly of human amylin.
Human amylin forms fibrillar amyloid between pancreatic islet cells in patients with non-insulin-dependent (type 2) diabetes mellitus. Fibrillar assemblies also form in vitro in aqueous solutions of synthetic human amylin. We now report on the structural polymorphism of these fibrils. The thinnest fibril, referred to as the protofibril, has an apparent width of 5 nm but is only rarely observed by itself. These protofibrils spontaneously assemble into higher order fibrillar structures with distinct morphologies. Prominent among these is an 8-nm fibril with a distinct 25-nm axial crossover repeat which is formed by left-handed coiling of two 5-nm protofibrils. Coiling of more than two 5-nm protofibrils results in cable-like structures of variable width depending on the number of protofibrils involved. Lateral (side-by-side) assembly of 5-nm protofibrils is also observed and produces ribbons which may contain two, three, four, or more protofibrils and occasionally large single-layered sheets. The mass-per-length (MPL) of the 5-nm protofibril is 10 kDa/nm. This has been established in two ways: first, the 8-nm fibril, which is formed by coiling two 5-nm protofibrils around each other, has an MPL of 20 kDa/nm. Second, higher order fibrils differ by increments of 10 kDa/nm. Hence, about 2.6 human amylin molecules (3904 Da) are packed in 1 nm of protofibril length. Similarities exist between amylin fibrils and those formed from other amyloid proteins, suggesting that the in vitro assembly of synthetic protein may serve as a useful model system in advancing our understanding of amyloid formation in disease.
Goldsbury
C S
CS
School of Biological Sciences, University of Auckland, New Zealand.
Cooper
G J
GJ
Goldie
K N
KN
Müller
S A
SA
Saafi
E L
EL
Gruijters
W T
WT
Misur
M P
MP
Engel
A
A
Aebi
U
U
Kistler
J
J
D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure*; D006801:Humans; D058228:Islet Amyloid Polypeptide; D008854:Microscopy, Electron; D008958:Models, Molecular; D010316:Particle Size; D011487:Protein Conformation
D000682:Amyloid; D058228:Islet Amyloid Polypeptide