Dioxygen binding is controlled by the protein environment in non-heme FeII and 2-oxoglutarate oxygenases: a study on histone demethylase PHF8 and an ethylene-forming enzyme

Invited for the cover of this issue are Christo Z. Christov and co-workers at Michigan Technological University, University of Oxford, and Michigan State University. The image depicts the oxygen diffusion channel in class 7 histone demethylase (PHF8) and ethylene-forming enzyme (EFE) and changes in the enzymes’ conformations upon binding. Read the full text of the article at 10.1002/chem.202300138

UNBOUND

Unbound showcases the graduating class from the fashion design school at Fanshawe College. Unbound describes the creative spirit and achievements of our twenty-seven emerging Canadian fashion designers. Unbound 2014 is a professional collaboration between Fanshawe College, Community and Professionals in the Fashion Industry. As you turn the pages, admire their accomplishments - the results of three years of passion, hard work, and dedication.https://first.fanshawec.ca/famd_design_fashiondesign_unbound/1003/thumbnail.jp

Conformational dynamics of alpha-synuclein:insights from mass spectrometry

The aggregation and deposition of alpha-synuclein in Lewy bodies is associated with the progression of Parkinson's disease. Here, Mass Spectrometry (MS) is used in combination with Ion Mobility (IM), chemical crosslinking and Electron Capture Dissociation (ECD) to probe transient structural elements of alpha-synuclein and its oligomers. Each of these reveals different aspects of the conformational heterogeneity of this 14 kDa protein. IM-MS analysis indicates that this protein is highly disordered, presenting in positive ionisation mode with a charge state range of 5 <= z <= 21 for the monomer, along with a collision cross section range of similar to 1600 angstrom(2)). Chemical crosslinking applied in conjunction with IM-MS captures solution phase conformational families enabling comparison with those exhibited in the gas phase. Crosslinking IM-MS identifies 3 distinct conformational families, Compact (similar to 1200 angstrom(2)), Extended (similar to 1500 angstrom(2)) and Unfolded (similar to 2350 angstrom(2)) which correlate with those observed in solution. ECD-Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry (ECD-FT-ICR MS) highlights the effect of pH on alpha-synuclein structure, identifying the conformational flexibility of the N and C termini as well as providing evidence for structure in the core and at times the C terminus. A hypothesis is proposed for the variability displayed in the structural rearrangement of alpha-synuclein following changes in solution pH. Following a 120 h aggregation time course, we observe an increase in the ratio of dimer to monomer, but no gross conformational changes in either, beyond the significant variations that are observed day-to-day from this conformationally dynamic protein

Dioxygen Binding Is Controlled by the Protein Environment in Non-heme Fe\u3csup\u3eII\u3c/sup\u3e and 2-Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene-Forming Enzyme

This study investigates dioxygen binding and 2-oxoglutarate (2OG) coordination by two model non-heme FeII/2OG enzymes: a class 7 histone demethylase (PHF8) that catalyzes the hydroxylation of its H3K9me2 histone substrate leading to demethylation reactivity and the ethylene-forming enzyme (EFE), which catalyzes two competing reactions of ethylene generation and substrate l-Arg hydroxylation. Although both enzymes initially bind 2OG by using an off-line 2OG coordination mode, in PHF8, the substrate oxidation requires a transition to an in-line mode, whereas EFE is catalytically productive for ethylene production from 2OG in the off-line mode. We used classical molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM) MD and QM/MM metadynamics (QM/MM-MetD) simulations to reveal that it is the dioxygen binding process and, ultimately, the protein environment that control the formation of the in-line FeIII-OO⋅− intermediate in PHF8 and the off-line FeIII-OO⋅− intermediate in EFE