Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators

Rupesh Kumar; Thirumurthy Madhavan; Kalaiarasan Ponnusamy; Honglae Sohn; Shazia Haider

doi:10.3389/fgene.2023.1282234

Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators

Front Genet. 2023 Nov 10:14:1282234. doi: 10.3389/fgene.2023.1282234. eCollection 2023.

Authors

Rupesh Kumar¹, Thirumurthy Madhavan², Kalaiarasan Ponnusamy³, Honglae Sohn⁴, Shazia Haider⁵

Affiliations

¹ Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India.
² Department of Genetic Engineering, Computational Biology Lab, SRM Institute of Science and Technology, Chennai, India.
³ Biotechnology Divison, National Centre for Disease Control, New Delhi, India.
⁴ Department of Chemistry and Department of Carbon Materials, Chosun University, Gwangju, Republic of Korea.
⁵ Department of Biosciences, Jamia Millia University, New Delhi, India.

Abstract

Introduction: Kinesin family member 5A (KIF5A) is a motor neuron protein expressed in neurons and involved in anterograde transportation of organelles, proteins, and RNA. Variations in the KIF5A gene that interfere with axonal transport have emerged as a distinguishing feature in several neurodegenerative disorders, including hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), and Amyotrophic Lateral Sclerosis (ALS). Methods: In this study, we implemented a computational structural and systems biology approach to uncover the role of KIF5A in ALS. Using the computational structural biology method, we explored the role of non-synonymous Single Nucleotide Polymorphism (nsSNPs) in KIF5A. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS. Results: We found KIF5A^S291F variant showed the most structure destabilizing behavior and the phytocompound "epigallocatechin gallate" showed the highest binding affinity (-9.0 Kcal/mol) as compared to wild KIF5A (-8.4 Kcal/mol). Further, with the systems biology approach, we constructed the KIF5A protein-protein interaction (PPI) network to identify the associated Kinesin Families (KIFs) proteins, modules, and their function. We also constructed a transcriptional and post-transcriptional regulatory network of KIF5A. With the network topological parameters of PPIN (Degree, Bottleneck, Closeness, and MNC) using CytoHubba and computational knock-out experiment using Network Analyzer, we found KIF1A, 5B, and 5C were the significant proteins. The functional modules were highly enriched with microtubule motor activity, chemical synaptic transmission in neurons, GTP binding, and GABA receptor activity. In regulatory network analysis, we found KIF5A post-transcriptionally down-regulated by miR-107 which is further transcriptionally up-regulated by four TFs (HIF1A, PPARA, SREBF1, and TP53) and down-regulated by three TFs (ZEB1, ZEB2, and LIN28A). Discussion: We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and KIF5A associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases.

Keywords: amyotrophic lateral sclerosis; kinesin family member 5A; miRNA; neurodegenerative diseases; nonsynonymous single-nucleotide polymorphisms; phytochemicals; protein‐protein interaction; transcription factor.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported (in part) by research funds from Chosun University, 2023.