Homology Modeling of Tubulin Isotypes to Investigate MT-Tau Interactions

Abstract

The Homology modeling techniques uses the template structure(s) to model the full-length structure of unknown sequence. It is being used for determining the structure of biological macromolecules, especially proteins. The wide applications of homology modeling approach have helped us to address various challenging problems in the field of biological sciences and drug discovery despite the limitations in using analytical techniques like X-ray, NMR and CryoEM techniques. Here, this chapter emphasize on application of homology modeling in determining MT-Tau interactions which are important in the Alzheimer disease. In Alzheimer diseases, tau detaches from MTs in misfolded shape and forms insoluble aggregates in neurons due to post-translational modifications. MT-tau interactions are largely unknown due to differential expression of neuronal specific tubulin isotypes and intrinsically disordered nature of tau. MTs play crucial roles in important cellular functions including cell division, transport of vesicles, cell signaling, cell motility etc. MTs are composed of different tubulin isotypes which differs mainly at C-terminal tail. In humans, nine β-tubulin isotypes have been reported which are expressed differently in different tissues. Structures for different tubulin isotypes are still lacking due to their complex differential expression pattern and purification. Hence, homology modeling approach allowed us to generate homology models for different neuronal specific tubulin isotypes and study their interactions with tau repeats. It is believed that this study would gain more structural and functional insights to the linked Alzheimer diseases.