Mobility and Core-Protein Binding Patterns of Disordered C‑Terminal Tails in β‑Tubulin Isotypes

• Published in: Biochemistry (Easton) 2017-03, Vol.56 (12), p.1746-1756
• Main Authors: Laurin, Yoann, Eyer, Joel, Robert, Charles H, Prevost, Chantal, Sacquin-Mora, Sophie
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antineoplastic Agents - chemistry; Binding Sites; Biochemistry, Molecular Biology; Biophysics; Humans; Life Sciences; Molecular Dynamics Simulation; Neurofilament Proteins - chemistry; Peptide Fragments - chemistry; Protein Binding; Protein Domains; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Multimerization; Protein Structure, Secondary; Sequence Alignment; Static Electricity; Structural Homology, Protein; Structure-Activity Relationship; Tubulin - chemistry; Tubulin - metabolism
• ISSN: 0006-2960; 1608-3040; 1520-4995
• DOI: 10.1021/acs.biochem.6b00988

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 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 isotype, 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 new perspectives for the development of isotype-specific chemotherapy drugs.