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6zpd
From Proteopedia
gamma-tocopherol transfer protein
Structural highlights
DiseaseTTPA_HUMAN Defects in TTPA are the cause of ataxia with isolated vitamin E deficiency (AVED) [MIM:277460. AVED is an autosomal recessive disease characterized by spinocerebellar degeneration. It causes ataxia and peripheral neuropathy that resembles Friedreich ataxia. AVED patients have markedly reduced plasma levels of vitamin E.[1] [2] [3] [4] [5] [6] FunctionTTPA_HUMAN Binds alpha-tocopherol and enhances its transfer between separate membranes. Publication Abstract from PubMedalpha-tocopherol transfer protein (TTP) was previously reported to self-aggregate into 24-meric spheres (alpha-TTP(S)) and to possess transcytotic potency across mono-layers of human umbilical vein endothelial cells (HUVECs). In this work, we describe the characterisation of a functional TTP variant with its vitamer selectivity shifted towards gamma-tocopherol. The shift was obtained by introducing an alanine to leucine substitution into the substrate-binding pocket at position 156 through site directed mutagenesis. We report here the X-ray crystal structure of the gamma-tocopherol specific particle (gamma-TTP(S)) at 2.24 A resolution. gamma-TTP(S) features full functionality compared to its alpha-tocopherol specific parent including self-aggregation potency and transcytotic activity in trans-well experiments using primary HUVEC cells. The impact of the A156L mutation on TTP function is quantified in vitro by measuring the affinity towards gamma-tocopherol through micro-differential scanning calorimetry and by determining its ligand-transfer activity. Finally, cell culture experiments using adherently grown HUVEC cells indicate that the protomers of gamma-TTP, in contrast to alpha-TTP, do not counteract cytokine-mediated inflammation at a transcriptional level. Our results suggest that the A156L substitution in TTP is fully functional and has the potential to pave the way for further experiments towards the understanding of alpha-tocopherol homeostasis in humans. Engineering of a functional gamma-tocopherol transfer protein.,Aeschimann W, Kammer S, Staats S, Schneider P, Schneider G, Rimbach G, Cascella M, Stocker A Redox Biol. 2021 Jan;38:101773. doi: 10.1016/j.redox.2020.101773. Epub 2020 Nov , 4. PMID:33197771[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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