Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators
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 neurodegene...
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2023.1282234/full |
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| author | Rupesh Kumar Thirumurthy Madhavan Kalaiarasan Ponnusamy Honglae Sohn Shazia Haider |
| author_facet | Rupesh Kumar Thirumurthy Madhavan Kalaiarasan Ponnusamy Honglae Sohn Shazia Haider |
| author_sort | Rupesh Kumar |
| collection | DOAJ |
| description | 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 KIF5AS291F 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. |
| first_indexed | 2024-03-11T10:54:19Z |
| format | Article |
| id | doaj.art-9763f1c8fa7d4214a8c7a7f0cdc24a8c |
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| language | English |
| last_indexed | 2024-03-11T10:54:19Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj.art-9763f1c8fa7d4214a8c7a7f0cdc24a8c2023-11-13T11:55:19ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-11-011410.3389/fgene.2023.12822341282234Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulatorsRupesh Kumar0Thirumurthy Madhavan1Kalaiarasan Ponnusamy2Honglae Sohn3Shazia Haider4Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, IndiaDepartment of Genetic Engineering, Computational Biology Lab, SRM Institute of Science and Technology, Chennai, IndiaBiotechnology Divison, National Centre for Disease Control, New Delhi, IndiaDepartment of Chemistry and Department of Carbon Materials, Chosun University, Gwangju, Republic of KoreaDepartment of Biosciences, Jamia Millia University, New Delhi, IndiaIntroduction: 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 KIF5AS291F 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.https://www.frontiersin.org/articles/10.3389/fgene.2023.1282234/fullneurodegenerative diseasesamyotrophic lateral sclerosiskinesin family member 5Anonsynonymous single-nucleotide polymorphismsprotein‐protein interactionphytochemicals |
| spellingShingle | Rupesh Kumar Thirumurthy Madhavan Kalaiarasan Ponnusamy Honglae Sohn Shazia Haider Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators Frontiers in Genetics neurodegenerative diseases amyotrophic lateral sclerosis kinesin family member 5A nonsynonymous single-nucleotide polymorphisms protein‐protein interaction phytochemicals |
| title | Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators |
| title_full | Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators |
| title_fullStr | Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators |
| title_full_unstemmed | Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators |
| title_short | Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators |
| title_sort | computational study of the motor neuron protein kif5a to identify nssnps bioactive compounds and its key regulators |
| topic | neurodegenerative diseases amyotrophic lateral sclerosis kinesin family member 5A nonsynonymous single-nucleotide polymorphisms protein‐protein interaction phytochemicals |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2023.1282234/full |
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