Yazar "Kang, David E." seçeneğine göre listele

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    Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10
    (Bentham Science Publ Ltd, 2024) Alici, Hakan; Uversky, Vladimir N.; Kang, David E.; Woo, Junga Alexa; Coskuner-Weber, Orkid
    Introduction The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10Q108P proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools.Method This study presents the foundational characterization of the structural features of CHCHD10Q108P and compares them with those of the wild-type counterpart. We conducted multiple run molecular dynamics simulations and bioinformatics analyses.Result Our findings reveal distinct differences in structural properties, free energy surfaces, and the outputs of principal component analysis between these two proteins. These results contribute significantly to the comprehension of CHCHD10 and its Q108P variant in terms of pathology, biochemistry, and structural biology.Conclusion The reported structural properties hold promise for informing the development of more effective treatments for ALS.
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    Effects of the Jokela type of spinal muscular atrophy-relatedG66V mutation on the structural ensemble characteristics ofCHCHD10
    (2023) Alıcı, Hakan; Uversky, Vladimir N.; Kang, David E.; Woo, Junga Alexa; Coşkuner Weber, Orkid
    The G66V pathological variant of the coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), mitochondrial, plays a role in Jokela type spinalmuscular atrophy. The wild-type and G66V mutant-type CHCHD10 proteins containintrinsically disordered regions, and therefore, their structural ensemble studies havebeen experiencing difficulties using conventional tools. Here, we show our resultsregarding the first characterization of the structural ensemble characteristics of theG66V mutant form of CHCHD10 and the first comparison of these characteristicswith the structural ensemble properties of wild-type CHCHD10. We find that thestructural properties, potential of mean force surfaces, and principal component anal-ysis show stark differences between these two proteins. These results are importantfor a better pathology, biochemistry and structural biology understanding ofCHCHD10 and its G66V genetic variant and it is likely that these reported structuralproperties are important for designing more efficient treatments for the Jokela typeof spinal muscular atrophy disease.
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    Frontotemporal dementia-related V57E mutation impairs mitochondrial function and alters the structural properties of CHCHD10
    (2023) Alıcı, Hakan; Uversky, Vladimir N.; Liu, Tian; Kang, David E.; Woo, Junga Alexa; Coşkuner Weber, Orkid
    The V57E pathological variant of the mitochondrial coiled-coil-helix–coiled-coil-helix domain-containing protein 10 (CHCHD10) plays a role in frontotemporal dementia. The wild-type and V57E mutant CHCHD10 proteins contain intrinsically disordered regions, and therefore, these regions hampered structural characterization of these proteins using conventional experimental tools. For the first time in the literature, we represent that the V57E mutation is pathogenic to mitochondria as it increases mitochondrial superoxide and impairs mitochondrial respiration. In addition, we represent here the structural ensemble properties of the V57E mutant CHCHD10 and describe the impacts of V57E mutation on the structural ensembles of wild-type CHCHD10 in aqueous solution. We conducted experimental and computational studies for this research. Namely, MitoSOX Red staining and Seahorse Mito Stress experiments, atomic force microscopy measurements, bioinformatics, homology modeling, and multiple-run molecular dynamics simulation computational studies were conducted. Our experiments show that the V57E mutation results in mitochondrial dysfunction, and our computational studies present that the structural ensemble properties of wild-type CHCHD10 are impacted by the frontotemporal dementia-associated V57E genetic mutation.
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    Structures of the Wild-Type and S59L Mutant CHCHD10 ProteinsImportant in Amyotrophic Lateral Sclerosis-FrontotemporalDementia
    (American Chemical Society, 2022) Alıcı, Hakan; Uversky, Vladimir N.; Kang, David E.; Woo, Junga Alexa; Weber, Orkide Coşkuner
    The S59L genetic mutation of the mitochondrial coiled-coil-helix-coiled-coil-helixdomain-containing protein 10 (CHCHD10) is involved in the pathogenesis of amyotrophic lateralsclerosis (ALS) and frontotemporal dementia (FTD). The wild-type and mutant forms of this proteincontain intrinsically disordered regions, and their structural characterization has been facing challenges.Here, for thefirst time in the literature, we present the structural ensemble properties of the wild-type andS59L mutant form of CHCHD10 in an aqueous solution environment at the atomic level with dynamics.Even though available experiments suggested that the S59L mutation may not change the structure of theCHCHD10 protein, our structural analysis clearly shows that the structure of this protein is significantlyaffected by the S59L mutation. We present here the secondary structure components with theirabundances per residue, the tertiary structure properties, the free energy surfaces based on the radius ofgyration and end-to-end distance values, the Ramachandran plots, the quantity of intramolecularhydrogen bonds, and the principal component analysis results. These results may be crucial in designingmore efficient treatment for ALS and FTD diseases.
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    The impacts of the mitochondrial myopathy-associated G58R mutation on the dynamic structural properties of CHCHD10
    (2023) Alıcı, Hakan; Uversky, Vladimir N.; Kang, David E.; Woo, Junga Alexa; Coşkuner Weber, Orkid
    The mitochondria are responsible for producing energy within the cell, and in mitochondrial myop-athy, there is a defect in the energy production process. The CHCHD10 gene codes for a protein calledcoiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), which is found in the mito-chondria and is involved in the regulation of mitochondrial function. G58R mutation has been shownto disrupt the normal function of CHCHD10, leading to mitochondrial dysfunction and ultimately tothe development of mitochondrial myopathy. The structures of G58R mutant CHCHD10 and howG58R mutation impacts the wild-type CHCHD10 protein at the monomeric level are unknown. Toaddress this problem, we conducted homology modeling, multiple run molecular dynamics simula-tions and bioinformatics calculations. We represent herein the structural ensemble properties of theG58R mutant CHCHD10 (CHCHD10G58R) in aqueous solution. Moreover, we describe the impacts ofG58R mutation on the structural ensembles of wild-type CHCHD10 (CHCHD10WT) in aqueous solution.The dynamics properties as well as structural properties of CHCHD10WTare impacted by the mitochon-drial myopathy-related G58R mutation. Specifically, the secondary and tertiary structure properties,root mean square fluctuations, Ramachandran diagrams and results from principal component analysisdemonstrate that the CHCHD10WTand CHCHD10G58Rproteins possess different structural ensemblecharacteristics and describe the impacts of G58R mutation on CHCHD10WT. These findings may behelpful for designing new treatments for mitochondrial myopathy.