Abstract
Rab10 is a small GTPase that regulates cellular processes by alternating between its GDP-bound inactive and the GTP-bound active states. Studies have shown that functional deficiencies in the Rab10 pathways are implicated in ciliophaties, gliobastomas and neurodegenerative diseases. Thus, the modulation of Rab10 activity may represent an interesting strategy in drug discovery. In order to identify potential Rab10 inhibitors for the treatment of Alzheimer’s disease, we studied the mobility of the switch1-interswitch-switch2 surface to understand the active “ON” and inactive “OFF” states of this enzyme. Even today, no in silico study on Rab10 linked to GTP and GDP has been carried out. We used molecular dynamics simulations to investigate the atomic movements of the Rab10 switch regions associated with these nucleotides. We found noticeable differences in the local flexibility of switch 1 when Rab10 was linked to GDP. However, the heuristic method used was not able to successfully differentiate the flexibility of switch 2 region. We hypothesized that the flexibility of the switch 1 region can be used as an indicator of in silico studies that search potential competitive inhibitors based on nucleotides against Rab10. Furthermore, the present study can be useful for research that involves the description on-to-off process of other target proteins.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Yan, T., Wang, L., Gao. J., et al.: Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer’s Disease. J. Alzheimer Dis. 63(1), 157–165 (2018)
Chua, C.E.L., Tang, B.L.: Rab10 – a traffic controller in multiple cellular pathways and locations. J. Cellular Phys. 233(9), 6483–6494 (2018)
Ordónez, A.J.L., Fernández, B., Fdez, E., et al.: RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase–mediated centrosomal cohesion and ciliogenesis deficits. Human Mol. Genetycs 28(21), 3552–3568 (2019)
Shen, G., Mao, Y., Su, Z., et al.: PSMB8-AS1 activated by ELK1 promotes cell proliferation in glioma via regulating miR-574-5p/RAB10. Biomed. Pharmacother. 122(1), 109658 (2020)
Ridge, P.G., Karch, C.M., Hsu, S., et al.: Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience. Genome Med. 9(1), 100 (2017)
Tavana, J.P., Rosene, M., Jensen, N.O., et al.: RAB10: an Alzheimer’s disease resilience locus and potential drug target. Clin. Interv. Aging 14(1), 73–79 (2019)
Good, R.G., Müller, M.P., Wu, Y.: Mechanisms of action of Rab proteins, key regulators of intracellular vesicular transport. Bio. Chem. 398(5–6), 565–575 (2017)
Pylypenko, O., Hammich, H., Yu, I., et al.: Rab GTPases and their interacting protein partners: Structural insights into Rab functional diversity. Small GTPases 9(1–2), 22–48 (2018)
Wang, J., Chou, K.: Insight into the molecular switch mechanism of human Rab5a from molecular dynamics simulations. Bio. Biophys. Res. Commun. 390(3), 608–612 (2009)
Rai, A., Oprisko, A., Campos, G., et al.: bMERB domains are bivalent Rab8 family effectors evolved by gene duplication. eLife 5(1), e186475 (2016)
Berman, H.M., Westbrook, J., Feng, et al.: The Protein Data Bank. Nucleic Acids Res. 28(1), 235–242 (2000)
Sali, A., Blundell, T.L.: Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234(1), 779–815 (1993)
O’Boyle, N.M., Banck, M., James, C.A., et al.: Open Babel: An open chemical toolbox. J. Cheminformatics 3(1), 33 (2011)
Trott, M., Olson, A.J.: AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31(1), 455–461 (2010)
Schrödinger Release 2020–3.: Maestro. New York NY (2020)
Spoel, D.V.D., Lindahl, E., Hess, B., et al.: GROMACS: Fast, flexible, and free. J. Comput. Chem. 26(1), 1701–1718 (2005)
Huang, J., MacKerell Jr., A.D.: CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. J. Comput. Chem. 34(1), 2135–2145 (2013)
Vanommeslaeghe, K., MacKerell Jr., A.D.: Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing. J. Chem. Inf. Model. 52(12), 3144–3154 (2012)
Paul, M., Panda, M.K., Thatoi, E.H.: Developing Hispolon-based novel anticancer therapeutics against human (NF-κβ) using in silico approach of modelling, docking and protein dynamics. J. Biomol. Struct. Dyn. 37(15), 3947–3967 (2019)
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this paper
Cite this paper
Alves, L.B., Castillo-Ordoñez, W.O., Giuliatti, S. (2020). Analyzing Switch Regions of Human Rab10 by Molecular Dynamics Simulations. In: Setubal, J.C., Silva, W.M. (eds) Advances in Bioinformatics and Computational Biology. BSB 2020. Lecture Notes in Computer Science(), vol 12558. Springer, Cham. https://doi.org/10.1007/978-3-030-65775-8_20
Download citation
DOI: https://doi.org/10.1007/978-3-030-65775-8_20
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-65774-1
Online ISBN: 978-3-030-65775-8
eBook Packages: Computer ScienceComputer Science (R0)