scholarly journals Missense Mutation Lys18Asn in Dystrophin that Triggers X-Linked Dilated Cardiomyopathy Decreases Protein Stability, Increases Protein Unfolding, and Perturbs Protein Structure, but Does Not Affect Protein Function

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e110439 ◽  
Author(s):  
Surinder M. Singh ◽  
Swati Bandi ◽  
Dinen D. Shah ◽  
Geoffrey Armstrong ◽  
Krishna M. G. Mallela
Keyword(s):  
Protein Structure ◽  
Dilated Cardiomyopathy ◽  
Protein Stability ◽  
Missense Mutation ◽  
Protein Function ◽  
Protein Unfolding ◽  
Affect Protein Function

scholarly journals Universal Screening Methods and Applications of ThermoFluor®

2006 ◽  
Vol 11 (7) ◽  
pp. 854-863 ◽  
Author(s):  
Maxwell D. Cummings ◽  
Michael A. Farnum ◽  
Marina I. Nelen
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Protein Unfolding ◽  
Direct Detection ◽  
Functional Characterization ◽  
Screening Methods ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Bacterial Enzyme ◽  
Research Problems

The genomics revolution has unveiled a wealth of poorly characterized proteins. Scientists are often able to produce milligram quantities of proteins for which function is unknown or hypothetical, based only on very distant sequence homology. Broadly applicable tools for functional characterization are essential to the illumination of these orphan proteins. An additional challenge is the direct detection of inhibitors of protein-protein interactions (and allosteric effectors). Both of these research problems are relevant to, among other things, the challenge of finding and validating new protein targets for drug action. Screening collections of small molecules has long been used in the pharmaceutical industry as 1 method of discovering drug leads. Screening in this context typically involves a function-based assay. Given a sufficient quantity of a protein of interest, significant effort may still be required for functional characterization, assay development, and assay configuration for screening. Increasingly, techniques are being reported that facilitate screening for specific ligands for a protein of unknown function. Such techniques also allow for function-independent screening with better characterized proteins. ThermoFluor®, a screening instrument based on monitoring ligand effects on temperature-dependent protein unfolding, can be applied when protein function is unknown. This technology has proven useful in the decryption of an essential bacterial enzyme and in the discovery of a series of inhibitors of a cancer-related, protein-protein interaction. The authors review some of the tools relevant to these research problems in drug discovery, and describe our experiences with 2 different proteins.

Binding of glutamine to glutamine-binding protein from Escherichia coli induces changes in protein structure and increases protein stability

2004 ◽  
Vol 58 (1) ◽  
pp. 80-87 ◽  
Author(s):  
Sabato D'Auria ◽  
Andrea Scirè ◽  
Antonio Varriale ◽  
Viviana Scognamiglio ◽  
Maria Staiano ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protein Structure ◽  
Protein Stability ◽  
Binding Protein

Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy☆

2006 ◽  
Vol 87 (2) ◽  
pp. 169-174 ◽  
Author(s):  
V VASILE ◽  
M WILL ◽  
S OMMEN ◽  
W EDWARDS ◽  
T OLSON ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Missense Mutation

scholarly journals A computational in silico approach to predict high-risk coding and non-coding SNPs of human PLCG1 gene

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260054
Author(s):  
Safayat Mahmud Khan ◽  
Ar-Rafi Md. Faisal ◽  
Tasnin Akter Nila ◽  
Nabila Nawar Binti ◽  
Md. Ismail Hosen ◽  
...  
Keyword(s):  
Protein Structure ◽  
T Cell ◽  
Protein Stability ◽  
In Silico ◽  
Catalytic Domain ◽  
Cell Lymphoma ◽  
Computational Study ◽  
Solvent Accessibility ◽  
T Cell Lymphoma ◽  
Post Translational Modification

PLCG1 gene is responsible for many T-cell lymphoma subtypes, including peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), cutaneous T-cell lymphoma (CTCL), adult T-cell leukemia/lymphoma along with other diseases. Missense mutations of this gene have already been found in patients of CTCL and AITL. The non-synonymous single nucleotide polymorphisms (nsSNPs) can alter the protein structure as well as its functions. In this study, probable deleterious and disease-related nsSNPs in PLCG1 were identified using SIFT, PROVEAN, PolyPhen-2, PhD-SNP, Pmut, and SNPS&GO tools. Further, their effect on protein stability was checked along with conservation and solvent accessibility analysis by I-mutant 2.0, MUpro, Consurf, and Netsurf 2.0 server. Some SNPs were finalized for structural analysis with PyMol and BIOVIA discovery studio visualizer. Out of the 16 nsSNPs which were found to be deleterious, ten nsSNPs had an effect on protein stability, and six mutations (L411P, R355C, G493D, R1158H, A401V and L455F) were predicted to be highly conserved. Among the six highly conserved mutations, four nsSNPs (R355C, A401V, L411P and L455F) were part of the catalytic domain. L411P, L455F and G493D made significant structural change in the protein structure. Two mutations-Y210C and R1158H had post-translational modification. In the 5’ and 3’ untranslated region, three SNPs, rs139043247, rs543804707, and rs62621919 showed possible miRNA target sites and DNA binding sites. This in silico analysis has provided a structured dataset of PLCG1 gene for further in vivo researches. With the limitation of computational study, it can still prove to be an asset for the identification and treatment of multiple diseases associated with the target gene.

scholarly journals Inference of Protein Function from Protein Structure

Structure ◽  
2005 ◽  
Vol 13 (1) ◽  
pp. 121-130 ◽  
Author(s):  
Debnath Pal ◽  
David Eisenberg
Keyword(s):  
Protein Structure ◽  
Protein Function

scholarly journals Cardiac-Specific Cre Induces Age-Dependent Dilated Cardiomyopathy (DCM) in Mice

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1189 ◽  
Author(s):  
Taha Rehmani ◽  
Maysoon Salih ◽  
Balwant Tuana
Keyword(s):  
Dna Damage ◽  
Dilated Cardiomyopathy ◽  
Protein Function ◽  
Mouse Genome ◽  
Model System ◽  
Dependent Manner ◽  
Cardiac Pathology ◽  
Damage Response ◽  
Age Dependent ◽  
Invaluable Tool

The genetic modification of the mouse genome using the cre-lox system has been an invaluable tool in deciphering gene and protein function in a temporal and/or spatial manner. However, it has its pitfalls, as researchers have shown that the unregulated expression of cre recombinase can cause DNA damage, the consequences of which can be very detrimental to mouse health. Previously published literature on the most utilized cardiac-specific cre, αMHC-cre, mouse model exhibited a nonlethal hypertrophic cardiomyopathy (HCM) with aging. However, using the same αMHC-cre mice, we observed a cardiac pathology, resulting in complete lethality by 11 months of age. Echocardiography and histology revealed that the αMHC-cre mice were displaying symptoms of dilated cardiomyopathy (DCM) by seven months of age, which ultimately led to their demise in the absence of any HCM at any age. Molecular analysis showed that this phenotype was associated with the DNA damage response through the downregulation of activated p38 and increased expression of JNK, p53, and Bax, known inducers of myocyte death resulting in fibrosis. Our data urges strong caution when interpreting the phenotypic impact of gene responses using αMHC-cre mice, since a lethal DCM was induced by the cre driver in an age-dependent manner in this commonly utilized model system.

scholarly journals A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kensuke Ihara ◽  
Tetsuo Sasano ◽  
Yuichi Hiraoka ◽  
Marina Togo-Ohno ◽  
Yurie Soejima ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Dilated Cardiomyopathy ◽  
Missense Mutation ◽  
Cardiac Dysfunction ◽  
Ventricular Arrhythmias ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Clinical State ◽  
Missense Mutations ◽  
Nuclear Localization Signals

Abstract Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.

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