Carbamylation promotes amyloidogenesis and induces structural changes in Tau-core hexapeptide fibrils

Show simple item record Guru, Krishnakumar Viswanathan Baweja, Lokesh Ralhan, Krittika Gupta, Sharad 2018-08-10T11:43:38Z 2018-08-10T11:43:38Z 2018-07
dc.identifier.citation Guru Krishnakumar, V.; Baweja, Lokesh; Ralhan, Krittika and Gupta, Sharad, “Carbamylation promotes amyloidogenesis and induces structural changes in Tau-core hexapeptide fibrils”, Biochimica et Biophysica Acta (BBA) - General Subjects, DOI: 10.1016/j.bbagen.2018.07.030, Vol.1862, No.12, pp. 2590-2604, Jul. 2018. en_US
dc.identifier.issn 03044165
dc.description.abstract Carbamylation is a non-enzymatic post-translational modification (PTM), which involves the covalent modification of N-terminus of protein or ε-amino group of Lys. The role of carbamylation in several age-related disorders is well documented, however, the relationship between carbamylation and neurodegenerative disorders including Alzheimer's disease remains uncharted METHODS: In the present study, using aggregation-prone tau-core hexapeptide fragments 306VQIVYK311 (PHF6) and 275VQIINK280 (PHF6*) as models, we have elucidated the effect of carbamylation on aggregation kinetics and the changes occurring in the 3-dimensional architecture of fibrils using biophysical assays and molecular dynamics simulations RESULTS: We found that carbamylation aids in amyloid formation and can convert the unstructured off-pathway aggregates into robust amyloids, which were toxic to cells. Electron microscopy images and molecular dynamics simulations of PHF6 fibrils showed that carbamylated peptides can form excess hydrogen bonds and modulate the pitch length and twist of peptides fibrils. We have also compared N-terminal carbamylation to acetylation and further extended our finding to full length tau that exhibits aggregation upon carbamylation even in the absence of any external inducer CONCLUSION: Our in vitro and in silico results together suggest that carbamylation can modulate the aggregation pathway of the amyloidegenic sequences and cause structural changes in fibril assemblies GENERAL SIGNIFICANCE: Carbamylation acts as a switch, which triggers the aggregation in short amyloidogenic peptide fragments and modulate the structural changes in resulting amyloid fibrils. en_US
dc.language.iso en_US en_US
dc.publisher Elsevier en_US
dc.subject Aggregation; Amyloids; Carbamylation; Peptide; Structural changes en_US
dc.subject Aggregation
dc.subject Amyloids
dc.subject Carbamylation
dc.subject Peptide
dc.subject Structural changes
dc.title Carbamylation promotes amyloidogenesis and induces structural changes in Tau-core hexapeptide fibrils en_US
dc.type Article en_US

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