Structural, functional and molecular dynamics analysis of the native and mutated actin to study its effect on congenital myopathy

Mohajer, Faeze Sadat; Parvizpour, Sepideh; Razmara, Jafar; Yazdi, Mahsa Khoshkhooy; Shamsir, Mohd Shahir

doi:10.1080/07391102.2016.1190299

Cited by 5 publications

(2 citation statements)

References 9 publications

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“…Over the years, various computational methods have been utilized for predicting the impact of mutations on protein structure and function (Capriotti, Fariselli, Rossi, & Casadio, 2008;Kumar, Doss, Sneha, Tayubi, Siva et al, 2017;Masso & Vaisman, 2008;Smith & Briggs, 2016). More recently, in silico computational studies using a molecular dynamics approach have successfully identified various structural perturbations that occur as a result of the mutation to assess structural instability (Ali, Sneha, Priyadharshini Christy, Zayed, & George Priya Doss, 2017;Sutthibutpong, Rattanarojpong, & Khunrae, 2017), protein dynamics (Mohajer, Parvizpour, Razmara, Khoshkhooy Yazdi, & Shamsir, 2017;Yang, Sang, Tao, Fu, Zhang et al, 2014), protein unfolding (Anwer, Sonani, Madamwar, Singh, Khan et al, 2015;Tompa & Kadhirvel, 2017), and impact on inter-domain interactions (Krishnamoorthy, Gajendrarao, Olivotto, & Yacoub, 2017). Therefore, acquiring an in-depth understanding of the impact of missense mutations on the structure of PTEN, and by extension, its function, is imperative to elucidating the molecular mechanisms underlying development of PTEN mutation-associated ASD and cancer.…”

Section: Introductionmentioning

confidence: 99%

Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes

Smith

Thacker

Jaini

et al. 2018

Journal of Biomolecular Structure and Dynamics

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Individuals with germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN), irrespective of clinical presentation, are diagnosed with PTEN hamartoma tumor syndrome (PHTS). PHTS confers a high risk of breast, thyroid, and other cancers or autism spectrum disorder (ASD) with macrocephaly. It remains unclear why mutations in one gene can lead to seemingly disparate phenotypes. Thus, we sought to identify differences in ASD vs. cancer-associated germline PTEN missense mutations by investigating putative structural effects induced by each mutation. We utilized a theoretical computational approach combining in silico structural analysis and molecular dynamics (MD) to interrogate 17 selected mutations from our patient population: six mutations were observed in patients with ASD (only), six mutations in patients with PHTS-associated cancer (only), four mutations shared across both phenotypes, and one mutation with both ASD and cancer. We demonstrate structural stability changes where all six cancer-associated mutations showed a global decrease in structural stability and increased dynamics across the domain interface with a proclivity to unfold, mediating a closed (inactive) active site. In contrast, five of the six ASD-associated mutations showed localized destabilization that contribute to the partial opening of the active site. Our results lend insight into distinctive structural effects of germline PTEN mutations associated with PTEN-ASD vs. those associated with PTEN-cancer, potentially aiding in identification of the shared and separate molecular features that contribute to autism or cancer, thus, providing a deeper understanding of genotype-phenotype relationships for germline PTEN mutations.

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Section: Introductionmentioning

confidence: 99%

Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes

Smith

Thacker

Jaini

et al. 2018

Journal of Biomolecular Structure and Dynamics

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“…In recent decades various computational methods have been launched for predicting the impacts of mutations on protein structure and function. These methods can successfully identify several structural and stability changes which occur in proteins due to mutations (Anwer et al, 2015; Sneha and Doss, 2016; Mohajer et al, 2017). The aim of this study was to assess the ability of diverse computational methods in predicting the missense variant induced alterations in amino acid sequence conservation, structural and functional features of RA candidate proteins.…”

Section: Introductionmentioning

confidence: 99%

Computational Molecular Phenotypic Analysis of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) Gene Mutations of Rheumatoid Arthritis

Shaik

Banaganapalli

2019

Front. Genet.

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Rheumatoid arthritis (RA) is a chronic autoimmune disorder of bone joints caused by the complex interplay between several factors like body physiology, the environment with genetic background. The recent meta-analysis of GWAS has expanded the total number of RA-associated loci to more than 100, out of which approximately ∼97% (98 variants) loci are located in non-coding regions, and the other ∼3% (3 variants) are in three different non-HLA genes, i.e., TYK2 (Prp1104Ala), IL6R (Asp358Ala), and PTPN22 (Trp620Arg). However, whether these variants prompt changes in the protein phenotype with regards to its stability, structure, and interaction with other molecules, remains unknown. Thus, we selected the three clinically pathogenic variants described above, as positive controls and applied diverse computational methods to scrutinize if those mutations cause changes in the protein phenotype. Both wild type and mutant protein structures of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) were modeled and studied for structural deviations. Furthermore, we have also studied the secondary structure characteristics, solvent accessibility and stability, and the molecular interaction deformities caused by the amino acid substitutions. We observed that simple nucleotide predictions of SIFT, PolyPhen, CADD and FATHMM yields mixed findings in screening the RA-missense variants which showed a ≥P-value threshold of 5 × 10−8 in genome wide association studies. However, structure-based analysis confirms that mutant structures shows subtle but significant changes at their core regions, but their functional domains seems to lose wild type like functional interaction. Our findings suggest that the multidirectional computational analysis of clinically potential RA-mutations could act as a primary screening step before undertaking functional biology assays.

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Molecular dynamics-based analyses of the structural instability and secondary structure of the fibrinogen gamma chain protein with the D356V mutation

Ali

Sneha

Christy

et al. 2016

Journal of Biomolecular Structure and Dynamics

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Mutations in the fibrinogen gamma chain (FGG) gene have been associated with various disorders, such as dysfibrinogenemia, thrombophilia, and hypofibrinogenemia. A literature survey showed that a residue exchange in fibrinogen Milano I from γ Asp to Val at position 330 impairs fibrin polymerization. The D356V (D330V) mutation located in the C-terminus was predicted to be highly deleterious and to affect the function of the protein. The pathogenicity of the altered gene and changes in protein functions were predicted using in silico methods, such as SIFT, PolyPhen 2, I-Mutant 3.0, Align GV-GD, PhD-SNP, and SNPs&GO. The secondary structure of the mutant protein was unwound by the end of the 50-ns simulation period, and a structural change in the helix-turn transition of the alpha-helical (352-356) region residues was observed. Moreover, a change in the length of the helical region was visualized in the mutant trajectory file, indicating the local transient unfolding of the protein. The obtained computational results suggest that the substitution of the neutral amino acid valine for the acidic amino acid aspartic acid at position 356 results in an unwound conformation within 50 ns, which might contribute to defective polymerization. Our analysis also provides insights into the effect of the conformational change in the D356V (D330V) mutant on protein structure and function.

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Structural, functional and molecular dynamics analysis of the native and mutated actin to study its effect on congenital myopathy

Cited by 5 publications

References 9 publications

Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes

Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes

Computational Molecular Phenotypic Analysis of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) Gene Mutations of Rheumatoid Arthritis

Molecular dynamics-based analyses of the structural instability and secondary structure of the fibrinogen gamma chain protein with the D356V mutation

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