Amyloid fibril formation from full-length and fragments of amylin

被引:286
作者
Goldsbury, C
Goldie, K
Pellaud, J
Seelig, J
Frey, P
Müller, SA
Kistler, J
Cooper, GJS
Aebi, U
机构
[1] Univ Basel, Biozentrum, ME Mueller Inst Struct Biol, CH-4056 Basel, Switzerland
[2] Univ Basel, Biozentrum, Dept Biophys Chem, CH-4056 Basel, Switzerland
[3] Univ Auckland, Sch Med, Dept Med, Auckland, New Zealand
[4] Univ Auckland, Sch Biol Sci, Auckland, New Zealand
[5] European Mol Biol Lab, Heidelberg, Germany
[6] Novartis Pharma AG, Basel, Switzerland
关键词
amyloid; fibril structure; polymorphism; amylin; IAPP; diabetes mellitus; transmission electron microscopy (TEM); scanning transmission electron microscopy (STEM); circular dichroism spectroscopy;
D O I
10.1006/jsbi.2000.4268
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Amyloid deposits of fibrillar human amylin (hA) in the pancreas may be a causative factor in type-2 diabetes. A detailed comparison of in vitro fibril formation by full-length hA(1-37) versus fragments of this peptide--hA(8-37) and hA(20-29)-is presented. Circular dichroism spectroscopy revealed that fibril formation was accompanied by a conformational change: random coil to beta-sheet/alpha-helical structure. Fibril morphologies were visualized by electron microscopy and displayed a remarkable diversity, hA(20-29) formed flat ribbons consisting of numerous 3.6-nm-wide protofibrils. In contrast, hA(1-37) and hA(8-37) formed polymorphic higher order fibrils by lateral association and/or coiling together of 5.0-nm-wide protofibril subunits. For full-length hA(1-37), the predominant fibril type contained three protofibrils and for hA(8-37), the predominant type contained two protofibrils. Polymerization was also monitored with the thioflavin-T binding assay, which revealed different kinetics of assembly for hA(1-37) and hA(8-37) fibrils. hA(20-29) fibrils did not bind thioflavin-T. Together the results demonstrate that the N-terminal region of the hA peptide influences the relative frequencies of the various higher order fibril types and thereby the overall kinetics of fibril formation, Furthermore, while residues 20-29 contribute to the fibrils' beta-sheet core, the flanking C- and N-terminal regions of the hA peptide determine the interactions involved in the formation of higher order coiled polymorphic superstructures. (C) 2000 Academic Press.
引用
收藏
页码:352 / 362
页数:11
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