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Carbamylation promotes amyloidogenesis and induces structural changes in Tau-core hexapeptide fibrils.
Guru KrishnaKumar, V; Baweja, Lokesh; Ralhan, Krittika; Gupta, Sharad.
Afiliación
  • Guru KrishnaKumar V; Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India.
  • Baweja L; Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India; Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA.
  • Ralhan K; Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India.
  • Gupta S; Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India. Electronic address: sharad@iitgn.ac.in.
Biochim Biophys Acta Gen Subj ; 1862(12): 2590-2604, 2018 12.
Article en En | MEDLINE | ID: mdl-30071272
BACKGROUND: 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Proteínas Portadoras / Proteínas tau / Carbamilación de Proteína / Amiloide Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Biochim Biophys Acta Gen Subj Año: 2018 Tipo del documento: Article País de afiliación: India Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Proteínas Portadoras / Proteínas tau / Carbamilación de Proteína / Amiloide Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Biochim Biophys Acta Gen Subj Año: 2018 Tipo del documento: Article País de afiliación: India Pais de publicación: Países Bajos