Post‐translational Chemical Modifications in Amyloid Fibril Formation

Abstract

Originally published in: Amyloid Proteins. Edited by Jean D. Sipe. Copyright © 2005 Wiley‐VCH Verlag GmbH & Co. KGaA Weinheim. Print ISBN: 3‐527‐31072‐X The sections in this article are Introduction Common Modifications that May Play a Significant Role In Vivo Cleavage by Proteases or Non‐enzymatic Hydrolysis Deamidation, Isomerization, Racemization and Protein l ‐Isoaspartyl Methyltransferase ( PIMT ) Oxidative Damage AGE s Phosphorylation Proposed Mechanisms by which Chemical Modifications may Affect Amyloid Deposition Conclusions Acknowledgments

Investigation of post-translational modifications in type 2 diabetes

“…The misfolding of proteins due to the contribution from PTMs is attracting attention also in the field of proteopathies [ 15 , 16 ]. The Type II diabetes mellitus is a protein conformation disorder because of the formation of beta-pleated sheets thereby aggregation resulting change in the tertiary structure of islet amyloid polypeptide proceeded by self-association and deposition of tissues [ 17 ].…”

Role of Site-Specific Asparagine Deamidation in Islet Amyloid Polypeptide Amyloidogenesis: Key Contributions of Residues 14 and 21

“…Non-enzymatic post-translational modifications (PTMs) of proteins are spontaneous covalent alterations, often irreversible, of residue side chains and/or polypeptide backbone. These PTMs, including glycation, nitration, and deamidation, can alter dramatically the structure, stability, dynamics, and/or aggregation propensity of proteins and can have profound biological implications. − Accumulated experimental evidence has highlighted the contributions of spontaneous PTMs in protein misfolding diseases associated with polypeptide aggregation and amyloid deposition . Glutamine and asparagine deamidation, the most common non-enzymatic PTM, is associated with amyloid assembly of many aggregation-prone polypeptides, including γD-crystallin related to cataracts, the amyloid-β (Aβ) peptide associated with Alzheimer’s disease, , the α-synuclein peptide related to Parkinson’s disease, and immunoglobulin light chain associated with AL amyloidosis .…”

“…1−3 Accumulated experimental evidence has highlighted the contributions of spontaneous PTMs in protein misfolding diseases associated with polypeptide aggregation and amyloid deposition. 4 Glutamine and asparagine deamidation, the most common non-enzymatic PTM, is associated with amyloid assembly of many aggregation-prone polypeptides, including γD-crystallin related to cataracts, 5 the amyloid-β (Aβ) peptide associated with Alzheimer's disease, 6,7 the α-synuclein peptide related to Parkinson's disease, 8 and immunoglobulin light chain associated with AL amyloidosis. 9 For instance, significant levels of Gln-3, Asn-7 (Tottori-Japanese mutant), and Asn-23 (Iowa mutant) deamidation were identified in ex vivo fibrils of Alzheimer's disease patients.…”

“…19 IAPP is a positively charged C-α-amidated peptide that displays no negative charge and three positive charges (Figure 1B). Considering that deamidation introduces a negative charge into the peptide sequence and that aggregation is usually favored when the net charge of the protein is closer to zero, 4,27 Asn deamidation is anticipated to have an effect on IAPP self-assembly.…”