Utilize este identificador para referenciar este registo:
https://hdl.handle.net/1822/80674
Título: | Acetylation and phosphorylation processes modulate Taus binding to microtubules: A molecular dynamics study |
Autor(es): | Castro, Tarsila Gabriel Ferreira, Tiago Matamá, Teresa Florentina-Daniela Munteanu Cavaco-Paulo, Artur |
Palavras-chave: | Tau Acetylation Phosphorylation Intrinsically disordered protein Molecular dynamics simulations Alzheimers disease |
Data: | Fev-2023 |
Editora: | Elsevier 1 |
Revista: | Biochimica et Biophysica Acta (BBA). General Subjects |
Citação: | Castro, T. G., Ferreira, T., Matamá, T., Munteanu, F.-D., & Cavaco-Paulo, A. (2023, February). Acetylation and phosphorylation processes modulate Tau’s binding to microtubules: A molecular dynamics study. Biochimica et Biophysica Acta (BBA) - General Subjects. Elsevier BV. http://doi.org/10.1016/j.bbagen.2022.130276 |
Resumo(s): | The microtubule-associated protein Tau has its normal function impaired when undergoing post-translational modifications. In this work, molecular modelling techniques were used to infer the effects of acetylation and phosphorylation in Tau's overall conformation, electrostatics, and interactions, but mostly in Tau's ability to bind microtubules. Reported harmful Lys sites were mutated by its acetylated form, generating eight different acetylated Tau (aTau) analogues. Similarly, phosphorylation sites found in normal brains and in Alzheimers lesioned brains were considered to design phosphorylated Tau (pTau) analogues. All these designed variants were evaluated in intracellular fluid and near a microtubule (MT) model. Our in silico findings demonstrated that the electrostatic changes, due to the absence of positive Lys charges in acetylation cases, or the increasingly negative charge in the phosphorylated forms, hamper the association to the MT tubulins in most cases. Post-translational modifications also pose very distinct conformations to the ones described for native Tau, which hinders the microtubule-binding region (MTBR) and turns difficult the expected binding. Our study elucidates important molecular processes behind Tau abnormal function which can inspire novel therapeutics to address Alzheimers disease. |
Tipo: | Artigo |
URI: | https://hdl.handle.net/1822/80674 |
DOI: | 10.1016/j.bbagen.2022.130276 |
ISSN: | 0304-4165 |
Versão da editora: | https://www.sciencedirect.com/science/article/pii/S0304416522001945 |
Arbitragem científica: | yes |
Acesso: | Acesso restrito UMinho |
Aparece nas coleções: | CEB - Publicações em Revistas/Séries Internacionais / Publications in International Journals/Series |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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document_55881_1.pdf Acesso restrito! | 3,64 MB | Adobe PDF | Ver/Abrir |