Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation

Alajmi, Mohamed F.; Khan, Shama; Choudhury, Arunabh; Noor, Saba; Hussain, Afzal; Lu, Wenying; Eapen, Mathew Suji; Chimankar, Vrushali; Hansbro, Philip M.; Sohal, Sukhwinder Singh; Elasbali, Abdelbaset Mohamed; Hassan, Imtaiyaz

doi:10.3389/fmolb.2021.780284

Cited by 12 publications

(9 citation statements)

References 59 publications

(34 reference statements)

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“…HOPE server suggests that V2074I and V2148A might disrupt the protein function as they are located near highly conserved region, whereas I2134T/A and Q2696H/R may not interfere protein function, as the mutant residues are more acceptable at these positions than the wild residue. In addition, researchers have studied the effect of point mutations on the stability of protein aided molecular dynamic simulation study [ 51 , 52 ]. It has been reported that I591D point mutation in alpha-dystroglycan caused instability of protein [ 51 ], whilst another study has reported less RMSD deviation in mutant models than wild model of serum and glucocorticoid-regulated kinase 1 (SGK1) protein [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, researchers have studied the effect of point mutations on the stability of protein aided molecular dynamic simulation study [ 51 , 52 ]. It has been reported that I591D point mutation in alpha-dystroglycan caused instability of protein [ 51 ], whilst another study has reported less RMSD deviation in mutant models than wild model of serum and glucocorticoid-regulated kinase 1 (SGK1) protein [ 52 ]. Zhang et al observed less deviation in wild type of human cytochrome P450 A2 protein than mutant F186L mutant model [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

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Mutational analysis of catalytic site domain of CCHFV L RNA segment

Kaushal

Baranwal

2023

J Mol Model

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Introduction Crimean-Congo haemorrhagic fever virus (CCHFV) has tripartite RNA genome and is endemic in various countries of Asia, Africa and Europe. Method The present study is focused on mutation profiling of CCHFV L segment and phylogenetic clustering of protein dataset into six CCHFV genotypes. Results Phylogenetic tree rooted with NCBI reference sequence (YP_325663.1) indicated less divergence from genotype III and the sequences belonging to same genotypes have shown less divergence among each other. Mutation frequency at 729 mutated positions was calculated and 563, 49, 33, 46 and 38 amino acid positions were found to be mutated at mutation frequency intervals of 0–0.2, 0.21–0.4, 0.41–0.6, 0.61–0.8 and 0.81–1.0 respectively. Thirty-eight highly frequent mutations (0.81–1.0 interval) were found in all genotypes and mapping in L segment (encoded for RdRp) revealed four mutations (V2074I, I2134T/A, V2148A and Q2695H/R) in catalytic site domain and no mutation in OTU domain. Molecular dynamic simulation and in silico analysis showed that catalytic site domain displayed large deviation and fluctuation upon introduction of these point mutations. Conclusion Overall study provides strong evidence that OTU domain is highly conserved and less prone to mutation whereas point mutations recorded in catalytic domain have affected the stability of protein and were found to be persistent in the large population. Supplementary Information The online version contains supplementary material available at 10.1007/s00894-023-05487-7.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mutational analysis of catalytic site domain of CCHFV L RNA segment

Kaushal

Baranwal

2023

J Mol Model

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“…Mutation in multiple kinases is the most general pathway that leads to tumors' development. [96][97][98][99][100][101] Mutated kinases are constitutively active and thus cause various cellular irregularities, leading to cancer initiation or growth. Mutation in signaling pathways leads to several diseases, including cancer and AD.…”

Section: Mark4 Mutationsmentioning

confidence: 99%

“…Mutation in multiple kinases is the most general pathway that leads to tumors’ development 96–101 . Mutated kinases are constitutively active and thus cause various cellular irregularities, leading to cancer initiation or growth.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of microtubule affinity‐regulating kinase 4 in cancer and neurodegenerative diseases

Alam,

Ahmed,

Abid

et al. 2023

J of Cellular Biochemistry

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Microtubule affinity‐regulating kinase 4 (MARK4) is a member of the Ser/Thr protein kinase family, phosphorylates the microtubule‐connected proteins and plays a vital role in causing cancers and neurodegenerative diseases. This kinase modulates multiple signaling pathways, including mammalian target of rapamycin, nuclear factor‐κB, and Hippo‐signaling, presumably responsible for cancer and Alzheimer's. MARK4 acts as a negative controller of the Hippo‐kinase cassette for promoting YAP/TAZ action, and the loss of MARK4 detains the tumorigenic properties of cancer cells. MARK4 is involved in tau hyperphosphorylation that consequently affects neurodegeneration. MARK4 is a promising drug target for cancer, diabetes, and Alzheimer's. Developing the potent and selective inhibitors of MAKR4 are promising in the therapeutic management of associated diseases. Despite its great significance, a few reviews are available to discuss its structure, function and clinical significance. In the current review, we aimed to provide detailed information on the structural features of MARK4 targeted in drug development and its role in various signaling pathways related to cancer and neurodegenerative diseases. We further described the therapeutic potential of MARK4 inhibitors in preventing numerous diseases. Finally, the updated information on MARK4 will be helpful in the further development of effective therapeutic molecules.

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“…PARK7 acts as both a causative and carcinogenic gene and plays a crucial role in oxidative stress [10]. Because mutations in PARK7 cause various complex diseases, we studied several variants of PARK7 using state-of-the-art computational approaches [12][13][14][15][16]. We took 152 mutations of the whole protein to explore their consequences in disease progression.…”

Section: Introductionmentioning

confidence: 99%

Impact of Single Amino Acid Substitutions in Parkinsonism-Associated Deglycase-PARK7 and Their Association with Parkinson’s Disease

Anjum

Joshia

Shafie

et al. 2022

JPM

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Parkinsonism-associated deglycase-PARK7/DJ-1 (PARK7) is a multifunctional protein having significant roles in inflammatory and immune disorders and cell protection against oxidative stress. Mutations in PARK7 may result in the onset and progression of a few neurodegenerative disorders such as Parkinson’s disease. This study has analyzed the non-synonymous single nucleotide polymorphisms (nsSNPs) resulting in single amino acid substitutions in PARK7 to explore its disease-causing variants and their structural dysfunctions. Initially, we retrieved the mutational dataset of PARK7 from the Ensembl database and performed detailed analyses using sequence-based and structure-based approaches. The pathogenicity of the PARK7 was then performed to distinguish the destabilizing/deleterious variants. Aggregation propensity, noncovalent interactions, packing density, and solvent accessible surface area analyses were carried out on the selected pathogenic mutations. The SODA study suggested that mutations in PARK7 result in aggregation, inducing disordered helix and altering the strand propensity. The effect of mutations alters the number of hydrogen bonds and hydrophobic interactions in PARK7, as calculated from the Arpeggio server. The study indicated that the alteration in the hydrophobic contacts and frustration of the protein could alter the stability of the missense variants of the PARK7, which might result in disease progression. This study provides a detailed understanding of the destabilizing effects of single amino acid substitutions in PARK7.

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Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation

Cited by 12 publications

References 59 publications

Mutational analysis of catalytic site domain of CCHFV L RNA segment

Mutational analysis of catalytic site domain of CCHFV L RNA segment

Therapeutic targeting of microtubule affinity‐regulating kinase 4 in cancer and neurodegenerative diseases

Impact of Single Amino Acid Substitutions in Parkinsonism-Associated Deglycase-PARK7 and Their Association with Parkinson’s Disease

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