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1.
Adv Protein Chem Struct Biol ; 141: 177-201, 2024.
Article in English | MEDLINE | ID: mdl-38960473

ABSTRACT

Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.


Subject(s)
Amyotrophic Lateral Sclerosis , Humans , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Gene Expression Profiling , Motor Neuron Disease/genetics , Motor Neuron Disease/metabolism
2.
J Biomol Struct Dyn ; : 1-12, 2023 Jun 19.
Article in English | MEDLINE | ID: mdl-37334725

ABSTRACT

Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by insufficient aspartylglucosaminidase (AGA) activity leading to chronic neurodegeneration. We utilized the PhosphoSitePlus tool to identify the AGA protein's phosphorylation sites. The phosphorylation was induced on the specific residue of the three-dimensional AGA protein, and the structural changes upon phosphorylation were studied via molecular dynamics simulation. Furthermore, the structural behaviour of C163S mutation and C163S mutation with adjacent phosphorylation was investigated. We have examined the structural impact of phosphorylated forms and C163S mutation in AGA. Molecular dynamics simulations (200 ns) exposed patterns of deviation, fluctuation, and change in compactness of Y178 phosphorylated AGA protein (Y178-p), T215 phosphorylated AGA protein (T215-p), T324 phosphorylated AGA protein (T324-p), C163S mutant AGA protein (C163S), and C163S mutation with Y178 phosphorylated AGA protein (C163S-Y178-p). Y178-p, T215-p, and C163S mutation demonstrated an increase in intramolecular hydrogen bonds, leading to greater compactness of the AGA forms. Principle component analysis (PCA) and Gibbs free energy of the phosphorylated/C163S mutation structures exhibit transition in motion/orientation than Wild type (WT). T215-p may be more dominant among these than the other studied phosphorylated forms. It might contribute to hydrolyzing L-asparagine functioning as an asparaginase, thereby regulating neurotransmitter activity. This study revealed structural insights into the phosphorylation of Y178, T215, and T324 in AGA protein. Additionally, it exposed the structural changes of the C163S mutation and C163S-Y178-p of AGA protein. This research will shed light on a better understanding of AGA's phosphorylated mechanism.Communicated by Ramaswamy H. Sarma.

3.
J Biomol Struct Dyn ; 40(4): 1571-1585, 2022 03.
Article in English | MEDLINE | ID: mdl-33034275

ABSTRACT

K-Ras is a small GTPase and acts as a molecular switch by recruiting GEFs and GAPs, and alternates between the inert GDP-bound and the dynamic GTP-bound forms. The amino acid at position 12 of K-Ras is a hot spot for oncogenic mutations (G12A, G12C, G12D, G12R, G12S, and G12V), disturbing the active fold of the protein, leading to cancer development. This study aimed to investigate the potential conformational changes induced by these oncogenic mutations at the 12th position, impairing GAP-mediated GTP hydrolysis. Comprehensive computational tools (iStable, FoldX, SNPeffect, DynaMut, and CUPSAT) were used to evaluate the effect of these six mutations on the stability of wild type K-Ras protein. The docking of GTP with K-Ras was carried out using AutoDock4.2, followed by molecular dynamics simulations. Furthermore, on comparison of binding energies between the wild type K-Ras and the six mutants, we have demonstrated that the G12A and G12V mutants exhibited the strongest binding efficiency compared to the other four mutants. Trajectory analyses of these mutations revealed that G12A encountered the least deviation, fluctuation, intermolecular H-bonds, and compactness compared to the wildtype, which was supported by the lower Gibbs free energy value. Our study investigates the molecular dynamics simulations of the mutant K-Ras forms at the 12th position, which expects to provide insights about the molecular mechanisms involved in cancer development, and may serve as a platform for targeted therapies against cancer. Communicated by Ramaswamy H. Sarma.


Subject(s)
Molecular Dynamics Simulation , Mutation, Missense , Guanosine Diphosphate/chemistry , Guanosine Triphosphate/chemistry , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism
4.
Plant Sci ; 310: 110991, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34315605

ABSTRACT

Carotenoids are economically valuable isoprenoids synthesized by plants and microorganisms, which play a paramount role in their overall growth and development. Carotenoid cleavage dioxygenases are a vast group of enzymes that specifically cleave thecarotenoids to produce apocarotenoids. Recently, CCDs are a subject of talk because of their contributions to different aspects of plant growth and due to their significance in the production of economically valuable apocarotenoids. Among them, CCD4 stands unique because of its versatility in performing metabolic roles. This review focuses on the multiple functionalities of CCD4 like pigmentation, volatile apocarotenoid production, stress responses, etc. Interestingly, through our literature survey we arrived at a conclusion that CCD4 could perform functions of other carotenoid cleaving enzymes.The metabolic engineering, transcriptomic, and computational approaches adopted to reveal the contributions of CCD4 were also considered here for the study.Phylogenetic analysis was performed to delve into the evolutionary relationships of CCD4 in different plant groups. A tree of 81CCD genes from 64 plant species was constructed, signifying the presence of well-conserved families. Gene structures were illustrated and the difference in the number and position of exons could be considered as a factor behind functional versatility and substrate tolerance of CCD4 in different plants.


Subject(s)
Plant Proteins/metabolism , Gene Expression Regulation, Plant/genetics , Gene Expression Regulation, Plant/physiology , Genomics/methods , Metabolic Engineering/methods , Phylogeny , Plant Proteins/genetics , Transcriptome/genetics
5.
Molecules ; 25(23)2020 Nov 26.
Article in English | MEDLINE | ID: mdl-33255942

ABSTRACT

Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1-242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.


Subject(s)
Calcium-Binding Proteins/chemistry , Filamins/chemistry , Microfilament Proteins/chemistry , Models, Molecular , Protein Domains , Chemical Phenomena , Dwarfism/etiology , Evolution, Molecular , Facies , Filamins/genetics , Filamins/metabolism , Genetic Variation , Humans , Molecular Dynamics Simulation , Mutation , Osteochondrodysplasias/etiology , Polymorphism, Single Nucleotide , Protein Conformation , Solvents/chemistry , Structure-Activity Relationship , Calponins
6.
Genes (Basel) ; 11(11)2020 10 25.
Article in English | MEDLINE | ID: mdl-33113859

ABSTRACT

(1) Aims: Diabesity, defined as diabetes occurring in the context of obesity, is a serious health problem that is associated with an increased risk of premature heart attack, stroke, and death. To date, a key challenge has been to understand the molecular pathways that play significant roles in diabesity. In this study, we aimed to investigate the genetic links between diabetes and obesity in diabetic individuals and highlight the role(s) of shared genes in individuals with diabesity. (2) Methods: The interactions between the genes were analyzed using the Search Tool for the Retrieval of Interacting Genes (STRING) tool after the compilation of obesity genes associated with type 1 diabetes (T1D), type 2 diabetes (T2D), and maturity-onset diabetes of the young (MODY). Cytoscape plugins were utilized for enrichment analysis. (3) Results: We identified 546 obesity genes that are associated with T1D, T2D, and MODY. The network backbone of the identified genes comprised 514 nodes and 4126 edges with an estimated clustering coefficient of 0.242. The Molecular Complex Detection (MCODE) generated three clusters with a score of 33.61, 16.788, and 6.783, each. The highest-scoring nodes of the clusters were AGT, FGB, and LDLR genes. The genes from cluster 1 were enriched in FOXO-mediated transcription of oxidative stress, renin secretion, and regulation of lipolysis in adipocytes. The cluster 2 genes enriched in Src homology 2 domain-containing (SHC)-related events triggered by IGF1R, regulation of lipolysis in adipocytes, and GRB2: SOS produce a link to mitogen-activated protein kinase (MAPK) signaling for integrins. The cluster 3 genes ere enriched in IGF1R signaling cascade and insulin signaling pathway. (4) Conclusion: This study presents a platform to discover potential targets for diabesity treatment and helps in understanding the molecular mechanism.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Obesity/genetics , Obesity/pathology , Adipocytes/metabolism , Angiotensinogen/genetics , Fibrinogen/genetics , Gene Regulatory Networks , Lipolysis/physiology , Oxidative Stress/genetics , Receptor, IGF Type 1/metabolism , Receptors, LDL/genetics , Renin/metabolism , Shc Signaling Adaptor Proteins/genetics
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