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Michael Brad Strader Wayne A. Hicks Tigist Kassa Eileen Singleton Jayashree Soman John S. Olson Mitchell J. Weiss Todd L. Mollan Michael T. Wilson Abdu I. Alayash 《The Journal of biological chemistry》2014,289(32):22342-22357
A pathogenic V67M mutation occurs at the E11 helical position within the heme
pockets of variant human fetal and adult hemoglobins (Hb). Subsequent
post-translational modification of Met to Asp was reported in γ subunits
of human fetal Hb Toms River (γ67(E11)Val → Met) and β
subunits of adult Hb (HbA) Bristol-Alesha (β67(E11)Val → Met) that
were associated with hemolytic anemia. Using kinetic, proteomic, and crystal
structural analysis, we were able to show that the Met → Asp
transformation involves heme cycling through its oxoferryl state in the
recombinant versions of both proteins. The conversion to Met and Asp enhanced
the spontaneous autoxidation of the mutants relative to wild-type HbA and human
fetal Hb, and the levels of Asp were elevated with increasing levels of hydrogen
peroxide (H2O2). Using
H218O2, we verified incorporation of
18O into the Asp carboxyl side chain confirming the role of
H2O2 in the oxidation of the Met side chain. Under
similar experimental conditions, there was no conversion to Asp at the
αMet(E11) position in the corresponding HbA Evans (α62(E11)Val
→ Met). The crystal structures of the three recombinant Met(E11) mutants
revealed similar thioether side chain orientations. However, as in the solution
experiments, autoxidation of the Hb mutant crystals leads to electron density
maps indicative of Asp(E11) formation in β subunits but not in α
subunits. This novel post-translational modification highlights the
nonequivalence of human Hb α, β, and γ subunits with
respect to redox reactivity and may have direct implications to
α/β hemoglobinopathies and design of oxidatively stable Hb-based
oxygen therapeutics. 相似文献
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Vitamin E is a mixture of eight compounds α, β, γ, δ tocopherols and α, β, γ, δ tocotrienols. Their individual
role in cellular transport as antioxidants and in metabolic pathways has been highlighted in the present work. All the eight compounds have been docked with the respective
metabolizing enzymes (αtocopherol transfer protein (ATTP), αtocopherol associated protein (TAP), Pglycoprotein (Pgly) and human serum albumin (HSA)) to understand
molecular interactions for pharmacokinetics. These have been structurally aligned against the four human phospholipids in order to reveal their individual role in chylomicron
formation and hence the mechanism of cellular transport. The study of their binding with their metabolizing enzymes provides insight to the comparative antioxidant activity of each
of these isomers. 相似文献
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Dual TCRα-expressing T cells outnumber dual TCRβ-expressing cells by ~10:1. As a result, efforts to understand how dual TCR T cells impact immunity have focused on dual TCRα expression; dual TCRβ expression remains understudied. We recently demonstrated, however, that dual TCRβ expression accelerated disease in a TCR transgenic model of autoimmune arthritis through enhanced positive selection efficiency, indicating that dual TCRβ expression, though rare, can impact thymic selection. Here we generated mice hemizygous for TCRα, TCRβ, or both on the C57BL/6 background to investigate the impact bi-allelic TCR chain recombination has on T cell development, repertoire diversity, and autoimmunity. Lack of bi-allelic TCRα or TCRβ recombination reduced αβ thymocyte development efficiency, and the absence of bi-allelic TCRβ recombination promoted γδ T cell development. However, we observed no differences in the numbers of naïve and expanded antigen-specific T cells between TCRα+/-β+/- and wildtype mice, and TCR repertoire analysis revealed only subtle differences in Vβ gene usage. Finally, the absence of dual TCR T cells did not impact induced experimental autoimmune encephalomyelitis pathogenesis. Thus, despite more stringent allelic exclusion of TCRβ relative to TCRα, bi-allelic TCRβ expression can measurably impact thymocyte development and is necessary for maintaining normal αβ/γδ T cell proportions. 相似文献
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Cristina Montero-Diez Padraig Deighan Joseph Osmundson Seth A. Darst Ann Hochschild 《Journal of bacteriology》2013,195(16):3621-3628
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