Conclusions
Our studies suggest that insoluble amyloid formation by IAPP follows kinetics that are consistent with a nucleation-dependent polymerization mechanism. Thus, IAPP amyloid formation can be accelerated by seeding with preformed IAPP amyloid fibrils. At the molecular level, IAPP amyloid formation was found to proceed via a conformational transition into hydrophobic β-sheet containing conformeric states.
The transition into β-sheets could also be seeded by IAPP fibrils and proceeded via formation of a structured state with strongly solvent-exposed hydrophobic patches. This amyloid ogenic state was found to be populated in both the temperature-and the denaturant-induced denaturation pathways of IAPP and led to formation of insoluble amyloid fibrils. Concentration dependence CD studies suggested that the partly folded amyloidogenic state may form by self-association of partially unfolded IAPP.
Based on these results and on the observed nucleation-dependent protein polymerization mechanism, we propose that partially unfolded IAPP and its self-associated forms may be in equilibrium with native or non-amyloidogenic IAPP conformers and act as early and soluble precursors of β-sheet and amyloid formation.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Brahms, S. and Brahms, J. (1980). Determination of Protein Secondary Structure in Solution by Vacuum Ultraviolet Circular Dichroism, J. Mol. Biol. 138, 149–178.
Colon, W. and Kelly, J. W. (1992). Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro, Biochemistry 31, 8654–8660.
Cooper, G. J. S., Willis, A. C., Clark, A., Turner, R. C., Sim, R. B. and Reid, K. B. M. (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients, Proc. Natl. Acad. Sci. U.S.A. 84, 8628–8632.
Goldberg, M. E., Rudolph, R. and Jaenicke, R. (1991). A kinetic study of the competition between renaturation and aggregation during the refolding of denaturated-reduced egg white lysozyme, Biochemistry 30, 2790–2797.
Harper, J. D. and Lansbury, P. T., Jr. (1997). Models of amyloid seeding in Alzheimer’s disease and scrapie: Mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins, Annu. Rev. Biochem. 66, 385–407.
Harper, J. D., Wong, S. S., Lieber, C. M. and Lansbury, P. T., Jr. (1997). Observation of metastable Aβ amyloid protofibrils by atomic force microscopy, Chem. Biol. 4, 119–125.
Jaenicke, R. and Rudolph, R. (1986). Refolding and association of oligomeric proteins, Methods Enzymol. 131, 218–250.
Jarrett, L. L. and Lansbury, P. T. J. (1993). Seeding one-dimensional crystallization of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie?, Cell 73, 1055–1058.
Jimenez, J. L., Guijarro, J. I., Orlova, E., Zurdo, J., Dobson, C. M., Sunde, M. and Saibil, H. R. (1999). Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing, Embo J. 18, 815–821.
Kapurniotu, A., Bernhagen, J., Greenfield, N., AI-Abed, Y., Teichberg, S., Frank, R. W., Voelter, W. and Bucala, R. (1998). Contribution of advanced glycosylation to the amyloidogenicity of islet amyloid polypeptide, Eur. J. Biochem. 251, 208–216.
Kayed, R., Bemhagen, J., Greenfield, N., Sweimeh, K., Brunner, H., Voelter, W. and Kapurniotu, A. (1999). Conformational transitions of islet amyloid polypeptide (IAPP) in amyloid formation in vitro, J. Mol. Biol. 287, 781–796.
Kim, P. S. and Baldwin, R. L. (1990). Intermediates in the folding reactions of small proteins, Annu. Rev. Biochem. 59, 631–660.
Lai, Z., Colon, W. and Kelly, J.W.(1996) Thea cid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid, Biochemistry 35, 6470–6482.
Lai, Z., McCulloch, J., Lashuel, H. A. and Kelly, J. W. (1997). Guanidine hydrochloride-induced denaturation and refolding of transthyretin exhibits a marked hysteresis: Equilibria with high kinetic barriers, Biochemistry 36, 10230–10239.
Lansbury, P. T., Jr. (1999). Evolution of amyloid: What normal protein folding may tell us about fibrillogenesis and disease, Proc. Natl. Acad. Sci. USA 96, 3342–3344.
Lansbury, P.T. Jr. (1992) In pursuit of the molecular structure of amyloid plaque: New technology provides unexpected and critical information, Biochemistry 31, 6865–6870.
Lorenzo, A., Razzboni, B., Weir, G. C. and Yankner B.A. (1994). Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus, Nature 368, 756–760.
Luskey, K. L. (1992). Possible links between amylin and diabetes, Diabetes Care 41, 297–299.
Maeda, H. (1987). Irreversible nature of the stacked β-pleated sheets of a model polypeptide, Bull. Chem. Soc. Jpn. 60, 3438–3440.
Maeda, H. and Ooi, K. (1981). Isodichroic point and the xβ-random coil transitionof poly(S-carboxymethyl-L-cystein) and poly(S-carboxyethyl-L-cysteine) in the absence of added salt, Biopolymers 20, 1549–1563.
Ptitsyn, 0. B. (1995). Molten globule and protein folding, Adv. Proein Chem. 47, 83–229.
Semisotnov, G. V., Rodionova, N. A., Razgulyaev, O. I., Uversky, V. N., Gripas, A. F. and Gilmanshin, R. I. (1991). Study of the “molten globule” intermediate state in protein folding by a hydrophobic fluorescent probe, Biopolymers 31, 119–128.
Shen, C.-L. and Murphy, R. M. (1995). Solvent effects on self-assembly of β-amyloid peptide, Biophys. J. 69, 640–651.
Sipe, J. D. (1994). Amyloidosis, Critical Reviews in Clinical Laboratory Sciences 31, 325–354.
Soto, C. and Frangione, B. (1995). Two conformational states of amyloid β-peptide: implications for the pathogenesis of Alzheimer’s disease, Neurosci. Letters 186, 115–118.
Thomas, P. J., Qu, B.-H. and Pedersen, P. L. (1995). Defective protein folding as a basis of human disease, Trends Biochem. Sci. 20, 456–459.
Westermark, P., Wernstedt, C., Wilander, E., Hayden, D. W., O’Brien, T. D. and Johnson, K. H. (1987). Amyloid fibrils in human insulinoma and islet of Lagerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells, Proc. Natl. Acad. Sci. USA 84, 3881–3885.
Wetzel, R. (1996). For protein misassembly it’s the “I” decade, Cell 86, 699–702.
Wood, S. J., Maleeff, B., Hart, T. and Wetzel, R. (1996). Physical, morphological and functional differences between pH 5.8 and 7.4 aggregates of the Alzheimer’s amyloid peptide Aβ J. Mol. Biol. 256, 870–877.
Woody, R. W. and Dunker, K. (1997). Aromatic and cystine side-chain circular dichroism in proteins, in G. D. Fasman (ed.), Circular Dichroism and the Conformational Analysis of Biomolecules. Plenum Press, New York and London, pp. 109–158.
Author information
Authors and Affiliations
Rights and permissions
Copyright information
© 2002 Kluwer Academic Publishers
About this chapter
Cite this chapter
Kapurniotu, A. (2002). Amyloidogenesis of Islet Amyloid Polypeptide (IAPP). In: Self-Assembling Peptide Systems in Biology, Medicine and Engineering. Springer, Dordrecht. https://doi.org/10.1007/0-306-46890-5_13
Download citation
DOI: https://doi.org/10.1007/0-306-46890-5_13
Publisher Name: Springer, Dordrecht
Print ISBN: 978-0-7923-7090-1
Online ISBN: 978-0-306-46890-2
eBook Packages: Springer Book Archive