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Protein Science (2002), 11:342-349.
Copyright © 2002 The Protein Society

Low levels of asparagine deamidation can have a dramatic effect on aggregation of amyloidogenic peptides: Implications for the study of amyloid formation

Melanie R. Nilsson1,3, Miles Driscoll1 and Daniel P. Raleigh1,2

1 Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA
2 Graduate Program in Biophysics and Graduate Program in Molecular and Cellular Biology, State University of New York at Stony Brook, Stony Brook, New York 11794, USA

Reprint requests to: Daniel P. Raleigh, Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400; e-mail: draleigh{at}notes.cc.sunysb.edu; fax: (631) 632-7960.

The polypeptide hormone amylin forms amyloid deposits in Type 2 diabetes mellitus and a 10-residue fragment of amylin (amylin20–29) is commonly used as a model system to study this process. Studies of amylin20–29 and several variant peptides revealed that low levels of deamidation can have a significant effect on the secondary structure and aggregation behavior of these molecules. Results obtained with a variant of amylin20–29, which has the primary sequence SNNFPAILSS, are highlighted. This peptide is particularly interesting from a technical standpoint. In the absence of impurities the peptide does not spontaneously aggregate and is not amyloidogenic. This peptide can spontaneously deamidate, and the presence of less than 5% of deamidation impurities leads to the formation of aggregates that have the hallmarks of amyloid. In addition, small amounts of deamidated material can induce amyloid formation by the purified peptide. These results have fundamental implications for the definition of an amyloidogenic sequence and for the standards of purity of peptides and proteins used for studies of amyloid formation.

Keywords: Amylin; islet amyloid polypeptide; IAPP; amyloid; deamidation; protein aggregation; diabetes mellitus; chemical modification

Abbreviations: ACN, acetonitrile • Asn, asparagine • Asp, aspartic acid • CCA, {alpha}-cyano-4-hydroxycinnamic acid • FTIR, Fourier transform infrared spectroscopy • isoAsp, isoaspartic acid • MALDI-MS, matrix-assisted laser desorption ionization mass spectrometry • RP-HPLC, reversed-phase high-performance liquid chromatography • TEM, transmission electron microscopy


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