T54R mutation destabilizes the dimer of superoxide dismutase 1<sup>T54R</sup> by inducing steric clashes at the dimer interface

Ghosh, Debasish Kumar; Kumar, Abhishek; Ranjan, Akash

doi:10.1039/c9ra09870d

Cited by 17 publications

(5 citation statements)

References 59 publications

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“…[ 30 ] LSPT often results in formation of amyloid fibrils [ 87 ] that induce cellular toxicity when mutations [ 88 ] or chemical changes [ 89 ] alter the structure or concentration of proteins, such as in the case of the SG proteins fused in Sarcoma (FUS), [ 90 ] TDP‐43 [ 91 ] and SOD1. [ 92 ] LSPT is rather a wide spread phenomenon [ 93 ] tightly linked to protein abundance. [ 7 ] Indeed, biophysical experiments [ 85 ] indicate that there is a critical concentration, specific for each protein, [ 94,95 ] above which aggregation is favored and formation of amyloid fibrils promoted.…”

Section: Rna Mediates Macromolecular Assembly In the Cellmentioning

confidence: 99%

RNA‐protein interactions: Central players in coordination of regulatory networks

et al. 2020

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Changes in the abundance of protein and RNA molecules can impair the formation of complexes in the cell leading to toxicity and death. Here we exploit the information contained in protein, RNA and DNA interaction networks to provide a comprehensive view of the regulation layers controlling the concentration‐dependent formation of assemblies in the cell. We present the emerging concept that RNAs can act as scaffolds to promote the formation ribonucleoprotein complexes and coordinate the post‐transcriptional layer of gene regulation. We describe the structural and interaction network properties that characterize the ability of protein and RNA molecules to interact and phase separate in liquid‐like compartments. Finally, we show that presence of structurally disordered regions in proteins correlate with the propensity to undergo liquid‐to‐solid phase transitions and cause human diseases. Also see the video abstract here https://youtu.be/kfpqibsNfS0

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Section: Rna Mediates Macromolecular Assembly In the Cellmentioning

confidence: 99%

RNA‐protein interactions: Central players in coordination of regulatory networks

et al. 2020

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“…Additionally, mutations impacting the β-sheet structures near edge-strands result in loss of stability and increased susceptibility to aggregation (54). Further evidence suggests variants affecting core and buried residues of SOD1 result in destabilization of interactions imperative for proper folding and in exposure of hydrophobic residues, which again induces aggregation (55)(56)(57)(58). Finally, aggregation of SOD1 was found to be prompted due to loss of and alteration in PTMs, such as copper and zinc binding, disulphide formation, phosphorylation, and ubiquitination, among others (59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes

Dilliott

Rouleau

Iqbal

et al. 2022

Preprint

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Background: Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3,864 individuals with ALS and 7,839 controls) and Project MinE ALS Sequencing Consortium (4,366 individuals with ALS and 1,832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes. Results: Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in β-sheets and α-helices, as well as in core, buried, or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and protein-protein interaction regions are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses to determine whether individual genes were driving the enrichment signal. A case study is presented forSOD1to demonstrate proof of concept of how enriched features may aid in defining variant pathogenicity. Conclusions: Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.

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“…The protein structures were corrected in the protein preparation wizard of Maestro 9.2 (Schrödinger Inc.) as carried out in our earlier studies. − The accurate structures of the proteins were generated by adding missing hydrogen atoms, making optimal protonation states of histidine residues, and assigning proper bond orders with the following refinement parameters–OPLS_2005 forcefield, convergence heavy atom to RMSD of 0.30 Å. This was followed by minimization of the structures in the Molecular Modelling Toolkit (MMTK) .…”

Section: Methodsmentioning

confidence: 99%

Differential Stabilities of Mefloquine-Bound Human and Plasmodium falciparum Acyl-CoA-Binding Proteins

2021

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Toxic effects of pharmacological drugs restrict their robust application against human diseases. Although used as a drug in the combinatorial therapy to treat malaria, the use of mefloquine is not highly recommended because of its adverse effects in humans. Mefloquine inhibits the binding of acyl-CoAs to acyl-CoA-binding proteins of Plasmodium falciparum (PfACBPs) and human (hACBP). In this study, we have used molecular dynamics simulation and other computational approaches to investigate the differences of stabilities of mefloquine–PfACBP749 and mefloquine–hACBP complexes. The stability of mefloquine in the binding cavity of PfACBP749 is less than its stability in the binding pocket of hACBP. Although the essential tyrosine residues (tyrosine-30 and tyrosine-33 of PfACBP749 and tyrosine-29 and tyrosine-32 of hACBP) mediate the initial binding of mefloquine to the proteins by π-stacking interactions, additional temporally longer interactions between mefloquine and aspartate-22 and methionine-25 of hACBP result in stronger binding of mefloquine to hACBP. The higher fluctuation of mefloquine-binding residues of PfACBP749 contributes to the instability of mefloquine in the binding cavity of the protein. On the contrary, in the mefloquine-bound state, the stability of hACBP protein is less than the stability of PfACBP749. The helix-to-coil transition of the N-terminal hydrophobic region of hACBP has a destabilizing effect upon the protein’s structure. This causes the induction of aggregation properties in the hACBP in the mefloquine-bound state. Taken together, we describe the mechanistic features that affect the differential dynamic stabilities of mefloquine-bound PfACBP749 and hACBP proteins.

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T54R mutation destabilizes the dimer of superoxide dismutase 1^T54R by inducing steric clashes at the dimer interface

Abstract: T54R mutation destabilizes the dimer of SOD1T54R.

Cited by 17 publications

References 59 publications

RNA‐protein interactions: Central players in coordination of regulatory networks

RNA‐protein interactions: Central players in coordination of regulatory networks

Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes

Differential Stabilities of Mefloquine-Bound Human and Plasmodium falciparum Acyl-CoA-Binding Proteins

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T54R mutation destabilizes the dimer of superoxide dismutase 1T54R by inducing steric clashes at the dimer interface

Abstract: T54R mutation destabilizes the dimer of SOD1T54R.

Cited by 17 publications

References 59 publications

RNA‐protein interactions: Central players in coordination of regulatory networks

RNA‐protein interactions: Central players in coordination of regulatory networks

Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes

Differential Stabilities of Mefloquine-Bound Human and Plasmodium falciparum Acyl-CoA-Binding Proteins

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T54R mutation destabilizes the dimer of superoxide dismutase 1^T54R by inducing steric clashes at the dimer interface