STRUCTURAL CHARACTERIZATION OF NPAS4-ARNT DIMERIZATION THROUGH COMPUTATIONAL SIMULATION
DOI:
https://doi.org/10.17501/25132695.2019.4102Keywords:
NPAS4, bHLH proteins, dimerization, neurotransmission, molecular simulationAbstract
Neuronal PAS Domain Protein 4 (Npas4) is an activity dependent transcription factor harboring basic helix-loop-helix (bHLH)-PAS domain, mediating the expression of target genes involved in neuro-transmission. NPAS4 crucially regulates response to various excitatory stimuli and has a role in GABAergic neuronal synapse development. Functionally, NPAS4 as a transcription factor dimerizes with the ARNT protein to serve as complete transcription factor and start the transcription of downstream genes. However, NPAS4 dimerization characteristics with ARNT has not been studied so far. Hence the current study aimed to identify the interaction pattern of NPAS4-ARNT complex through computational docking via HADDOCK. The interaction pattern were determined through pdbSum. The electrostatic surface calculations were performed through APBS plugins in PyMOL. The results indicated that PASB domain of NPAS4 is involved in interactions with the PAS B domain of ARNT. A toll of 136 structures generated by HADDOCK were further grouped into 14 clusters. The cluster with the minimum energy value of -82.6 KJ/mol was then further selected for interaction analysis. The results showed that there is one salt bridge, 12 H-bonding interactions and 156 non-bonded contacts between two proteins. The important interactions among two proteins are Asp224:NPAS4 and Gln421:ARNT, Asp229:NPAS4 and Ser442:ARNT, Glu232:NPAS4 and Thr361:ARNT, Phe240, Glu241:NPAS4, and Arg440:ARNT. The electrostatic potential of these two proteins revealed the binding interface of NPAS4 and ARNT to be neutral hence favoring hydrophobic interactions. The findings can help elucidate Npas4 role in interacting with other neuronal proteins involved in neuronal signaling. Moreover, the interaction findings provide useful comparative insight with other bHLH proteins.
Downloads
References
Yun, J., et al., Neuronal Per Arnt Sim (PAS) domain protein 4 (NPAS4) regulates neurite outgrowth and phosphorylation of synapsin I. J Biol Chem, 2013. 288(4): p. 2655-64.
Greer, P.L. and M.E. Greenberg, From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron, 2008. 59(6): p. 846-60.
Coutellier, L., et al., Npas4: a neuronal transcription factor with a key role in social and cognitive functions relevant to developmental disorders. PLoS One, 2012. 7(9): p. e46604.
Fahim, A., et al., Structural insights and characterization of human Npas4 protein. PeerJ, 2018. 6: p. e4978.
de Vries, S.J., M. van Dijk, and A.M. Bonvin, The HADDOCK web server for data-driven biomolecular docking. Nat Protoc, 2010. 5(5): p. 883-97.
Laskowski, R.A., PDBsum new things. Nucleic Acids Res, 2009. 37(Database issue): p. D355-9.
Ooe, N., et al., Identification of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 competitive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression. Mol Cell Biol, 2004. 24(2): p. 608-16.
Speckmann, T., et al., Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells. J Biol Chem, 2016. 291(6): p. 2682-95.
Moser, M., et al., LE-PAS, a novel Arnt-dependent HLH-PAS protein, is expressed in limbic tissues and transactivates the CNS midline enhancer element. Brain Res Mol Brain Res, 2004. 128(2): p. 141-9.
Kamnasaran, D., et al., Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J Med Genet, 2003. 40(5): p. 325-32.
Adachi, N., et al., New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases. World J Biol Chem, 2014. 5(4): p. 409-28.
Wu, D., et al., Structural integration in hypoxia-inducible factors. Nature, 2015. 524(7565): p. 303-8.
Wu, D., et al., NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors. Elife, 2016. 5.
Whitelaw, M., et al., Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor. Mol Cell Biol, 1993. 13(4): p. 2504-14.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
