Mobility and Core-Protein Binding Patterns of Disordered C-Terminal Tails in β-Tubulin Isotypes
| Autor: | Charles H. Robert, Sophie Sacquin-Mora, Chantal Prévost, Yoann Laurin, Joël Eyer |
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| Přispěvatelé: | Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Neurologie et Transgenèse UPRES EA3143 (LNBT), Université d'Angers (UA), Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire de Neurobiologie et Transgénèse (LNBT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Institut de biologie physico-chimique (IBPC (FR_550)) |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Static Electricity Protein domain Antineoplastic Agents Sequence alignment Plasma protein binding Molecular Dynamics Simulation Biochemistry Protein Structure Secondary Structure-Activity Relationship 03 medical and health sciences Protein structure Protein Domains Neurofilament Proteins Tubulin Microtubule Humans Protein Isoforms Amino Acid Sequence Homology modeling Binding Sites 030102 biochemistry & molecular biology biology computer.file_format Protein Data Bank Peptide Fragments [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biophysics Crystallography 030104 developmental biology Structural Homology Protein biology.protein Biophysics Protein Multimerization Sequence Alignment computer Protein Binding |
| Zdroj: | Biochemistry (mosc.) Biochemistry (mosc.), MAIK Nauka/Interperiodica : Springer Science+Business Media LLC, 2017, ⟨10.1021/acs.biochem.6b00988⟩ |
| ISSN: | 1520-4995 0006-2960 1608-3040 |
| Popis: | International audience; Although they play a significant part in the regulation of microtubule structure, dynamics and function, the disordered C-terminal tails of tubulin remain invisible to experimental structural methods and do not appear in the crystallographic structures that are currently available in the Protein Data Bank. Interestingly, these tails concentrate most of the sequence variability between tubulin isotypes, and are the sites of the principal post-translational modifications undergone by this protein. Using homology modeling, we developed two complete models for the human αI/βI and αI/βIII tubulin isotypes that include their C-terminal tails. We then investigated the conformational variability of the two β-tails using long time-scale classical Molecular Dynamics (MD) simulations that revealed similar features, notably the unexpected presence of common anchoring regions on the surface of the tuulin dimer, but also distinctive mobility or interaction patterns, some of which could be related to the tail lengths and charge distributions. We also observed in our simulations that the C-terminal tail from the βI isotype, but not the βIII, formed contacts in the putative binding site of a recently discovered peptide that disrupts microtubule formation in glioma cells. Hindering the binding site in the βI isotype would be consistent with this peptide’s preferential disruption of microtubule formation in glioma, whose cells overexpress βIII, compared to normal glial cells. While these observations need to be confirmed with more intensive sampling, our study opens up new perspectives for the development of isotype-specific chemotherapy drugs. |
| Databáze: | OpenAIRE |
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