scholarly journals Molecular Modeling of Pathogenic Mutations in the Keratin 1B Domain

2020 ◽  
Vol 21 (18) ◽  
pp. 6641 ◽  
Author(s):  
Alexander J. Hinbest ◽  
Sherif A. Eldirany ◽  
Minh Ho ◽  
Christopher G. Bunick
Keyword(s):  
Electrostatic Interactions ◽  
Phenotype Correlation ◽  
Molecular Alterations ◽  
Disease Phenotypes ◽  
Keratin 5 ◽  
Cytoskeletal Component ◽  
Altered Surface ◽  
Blistering Skin Disorders ◽  
Keratin Intermediate Filaments ◽  
Keratin 1

Keratin intermediate filaments constitute the primary cytoskeletal component of epithelial cells. Numerous human disease phenotypes related to keratin mutation remain mechanistically elusive. Our recent crystal structures of the helix 1B heterotetramer from keratin 1/10 enabled further investigation of the effect of pathologic 1B domain mutations on keratin structure. We used our highest resolution keratin 1B structure as a template for homology-modeling the 1B heterotetramers of keratin 5/14 (associated with blistering skin disorders), keratin 8/18 (associated with liver disease), and keratin 74/28 (associated with hair disorder). Each structure was examined for the molecular alterations caused by incorporating pathogenic 1B keratin mutations. Structural modeling indicated keratin 1B mutations can harm the heterodimer interface (R265PK5, L311RK5, R211PK14, I150VK18), the tetramer interface (F231LK1, F274SK74), or higher-order interactions needed for mature filament formation (S233LK1, L311RK5, Q169EK8, H128LK18). The biochemical changes included altered hydrophobic and electrostatic interactions, and altered surface charge, hydrophobicity or contour. Together, these findings advance the genotype-structurotype-phenotype correlation for keratin-based human diseases.

scholarly journals A Novel Keratin 5 Mutation (K5V186L) in a Family with EBS-K: a Conservative Substitution Can Lead to Development of Different Disease Phenotypes

2001 ◽  
Vol 116 (6) ◽  
pp. 964-969 ◽  
Author(s):  
Mirjana Liovic ◽  
Jure Stojan ◽  
Paul E. Bowden ◽  
Daniel Gibbs ◽  
Anders Vahlquist ◽  
...  
Keyword(s):  
Disease Phenotypes ◽  
Keratin 5

scholarly journals The Genomics of Myelodysplastic Syndromes: Origins of Disease Evolution, Biological Pathways, and Prognostic Implications

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2512
Author(s):  
Hassan Awada ◽  
Bicky Thapa ◽  
Valeria Visconte
Keyword(s):  
Experimental Studies ◽  
Gene Mutations ◽  
High Rate ◽  
Murine Models ◽  
Disease Evolution ◽  
Molecular Alterations ◽  
Disease Phenotypes ◽  
Prognostic Implications ◽  
Made In

The molecular pathogenesis of myelodysplastic syndrome (MDS) is complex due to the high rate of genomic heterogeneity. Significant advances have been made in the last decade which elucidated the landscape of molecular alterations (cytogenetic abnormalities, gene mutations) in MDS. Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis. Here, we summarize the genomics of MDS and provide an overview on the deregulation of pathways and the latest molecular targeted therapeutics.

scholarly journals Damaged Keratin Filament Network Caused by KRT5 Mutations in Localized Recessive Epidermolysis Bullosa Simplex

2021 ◽  
Vol 12 ◽  
Author(s):  
Fuying Chen ◽  
Lei Yao ◽  
Xue Zhang ◽  
Yan Gu ◽  
Hong Yu ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Mapk Signaling ◽  
Epidermolysis Bullosa Simplex ◽  
Protein Levels ◽  
Keratin 5 ◽  
Keratin Filament ◽  
Filament Network ◽  
Keratin Intermediate Filaments ◽  
Desmosomal Protein

Epidermolysis bullosa simplex (EBS) is a blistering dermatosis that is mostly caused by dominant mutations in KRT5 and KRT14. In this study, we investigated one patient with localized recessive EBS caused by novel homozygous c.1474T > C mutations in KRT5. Biochemical experiments showed a mutation-induced alteration in the keratin 5 structure, intraepidermal blisters, and collapsed keratin intermediate filaments, but no quantitative change at the protein levels and interaction between keratin 5 and keratin 14. Moreover, we found that MAPK signaling was inhibited, while desmosomal protein desmoglein 1 (DSG1) was upregulated upon KRT5 mutation. Inhibition of EGFR phosphorylation upregulated DSG1 levels in an in vitro model. Collectively, our findings suggest that this mutation leads to localized recessive EBS and that keratin 5 is involved in maintaining DSG1 via activating MAPK signaling.

scholarly journals Tailoring Surface Chemistry of Sugar-Derived Ordered Mesoporous Carbons towards Efficient Removal of Diclofenac from Aquatic Environments

Materials ◽  
2020 ◽  
Vol 13 (7) ◽  
pp. 1625 ◽  
Author(s):  
Rafał Olchowski ◽  
Emil Zięba ◽  
Dimitrios A. Giannakoudakis ◽  
Ioannis Anastopoulos ◽  
Ryszard Dobrowolski ◽  
...  
Keyword(s):  
Surface Chemistry ◽  
Electrostatic Interactions ◽  
Aquatic Environments ◽  
Efficient Removal ◽  
Water Contaminants ◽  
Ordered Mesoporous Carbons ◽  
Ordered Mesoporous ◽  
Desorption Study ◽  
Altered Surface ◽  
Treated Carbon

Ordered mesoporous carbon (CMK-3), obtained from an abundant natural source, sugar, was thermochemically modified with dicyandiamide and thiourea as well as by classical oxidization with hydrogen peroxide to introduce specific surface groups. Thermochemical modifications resulted in carbon with almost unchanged porosity and altered surface chemistry while porosity of H2O2-treated carbon was seriously deteriorated. The obtained carbons were tested as sorbents of diclofenac, considered as one of the emerging water contaminants. Changes in porosity and surface chemistry of modified carbons resulted in significant differences with regard to the uptake of diclofenac. Dicyandiamide-modified carbon showed highest uptake of drugs, reaching 241 mg g−1 that is attributed to its developed microporosity as well as surface chemistry composed of basic groups facilitating electrostatic interactions with diclofenac anions. Desorption study showed that diclofenac is strongly bonded, albeit with a different degree depending on the modification of the CMK-carbon. The obtained results were compared with up-to-date literature regarding sorption of diclofenac by carbon-based sorbents.

Genotype–phenotype correlation in Juvenile Paget disease: role of molecular alterations of the TNFRSF11B gene

Endocrine ◽  
2012 ◽  
Vol 42 (2) ◽  
pp. 266-271 ◽  
Author(s):  
Giacomina Brunetti ◽  
Flaviana Marzano ◽  
Silvia Colucci ◽  
Annamaria Ventura ◽  
Luciano Cavallo ◽  
...  
Keyword(s):  
Phenotype Correlation ◽  
Molecular Alterations ◽  
Paget Disease ◽  
Genotype Phenotype Correlation

Template mediated crystal engineering

1994 ◽  
Vol 52 ◽  
pp. 480-481
Author(s):  
Brigid R. Heywood ◽  
S. Champ
Keyword(s):  
Crystal Engineering ◽  
Electrostatic Interactions ◽  
Alkyl Chain ◽  
Crystallographic Axis ◽  
Two Dimensional ◽  
Engineering Process ◽  
Solution Interface ◽  
Extensive Program ◽  
Geometric Homology ◽  
Long Alkyl Chain

Recent work on the crystallisation of inorganic crystals under compressed monomolecular surfactant films has shown that two dimensional templates can be used to promote the oriented nucleation of solids. When a suitable long alkyl chain surfactant is cast on the crystallisation media a monodispersied population of crystals forms exclusively at the monolayer/solution interface. Each crystal is aligned with a specific crystallographic axis perpendicular to the plane of the monolayer suggesting that nucleation is facilitated by recognition events between the nascent inorganic solid and the organic template.For example, monolayers of the long alkyl chain surfactant, stearic acid will promote the oriented nucleation of the calcium carbonate polymorph, calcite, on the (100) face, whereas compressed monolayers of n-eicosyl sulphate will induce calcite nucleation on the (001) face, (Figure 1 & 2). An extensive program of research has confirmed the general principle that molecular recognition events at the interface (including electrostatic interactions, geometric homology, stereochemical complementarity) can be used to promote the crystal engineering process.

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