Adam J. Trexler

Bio: Adam J. Trexler is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Total internal reflection fluorescence microscope & Exocytosis. The author has an hindex of 15, co-authored 22 publications receiving 1065 citations. Previous affiliations of Adam J. Trexler include Yale University & University of Exeter.

α-Synuclein Binds Large Unilamellar Vesicles as an Extended Helix†

Abstract: Interactions between the synaptic protein α-Synuclein and cellular membranes may be relevant both to its native function as well as its role in Parkinson’s disease. We use single molecule Forster resonance energy transfer to probe the structure of α-Synuclein bound to detergent micelles and lipid vesicles. We find evidence that it forms a bent-helix when bound to highly curved detergent micelles, whereas it binds more physiological 100 nm diameter lipid vesicles as an elongated helix. Our results highlight the influence of membrane curvature in determining α-Synuclein conformation, which may be important for both its normal and disease-associated functions.

N-Terminal acetylation is critical for forming α-helical oligomer of α-synuclein.

Abstract: The aggregation of the protein α-synuclein (AS) is critical to the pathogenesis of Parkinson's disease. Although generally described as an unstructured monomer, recent evidence suggests that the native form of AS may be an α-helical tetramer which resists aggregation. Here, we show that N-terminal acetylation in combination with a mild purification protocol results in an oligomeric form of AS with partial α-helical structure. N-terminal acetylation of AS could have important implications for both the native and pathological structures and functions of AS. Through our demonstration of a recombinant expression system, our results represent an important step toward biochemical and biophysical characterization of this potentially important form of AS.

Allostery in a disordered protein: oxidative modifications to α-synuclein act distally to regulate membrane binding.

Abstract: Both oxidative stress and aggregation of the protein α-synuclein (aS) have been implicated as key factors in the etiology of Parkinson’s disease. Specifically, oxidative modifications to aS disrupt its binding to lipid membranes, an interaction considered critical to its native function. Here we seek to provide a mechanistic explanation for this phenomenon by investigating the effects of oxidative nitration of tyrosine residues on the structure of aS and its interaction with lipid membranes. Membrane binding is mediated by the first ∼95 residues of aS. We find that nitration of the single tyrosine (Y39) in this domain disrupts binding due to electrostatic repulsion. Moreover, we observe that nitration of the three tyrosines (Y125/133/136) in the C-terminal domain is equally effective in perturbing binding, an intriguing result given that the C-terminus is not thought to interact directly with the lipid bilayer. Our investigations show that tyrosine nitration results in a change of the conformational state...

Climate change in literature and literary criticism

Abstract: This article provides an overview of climate change in literature, focusing on the representation of climate change in Anglophone fiction. It then evaluates the way in which these fictional representations are critiqued in literary studies, and considers the extent to which the methods and tools that are currently employed are adequate to this new critical task. We explore how the complexity of climate change as both scientific and cultural phenomenon demands a corresponding degree of complexity in fictional representation. For example, when authors represent climate change as a global, networked, and controversial phenomenon, they move beyond simply employing the environment as a setting and begin to explore its impact on plot and character, producing unconventional narrative trajectories and innovations in characterization. Then, such creative complexity asks of literary scholars a reassessment of methods and approaches. For one thing, it may require a shift in emphasis from literary fiction to genre fiction. It also particularly demands that environmental criticism, or ecocriticism, moves beyond its long-standing interest in concepts of 'nature' and 'place', to embrace a new understanding of the local in relation to the global. We suggest, too, that there are synergies to be forged between these revisionary moves in ecocriticism and developments in literary critical theory and historicism, as these critical modes begin to deal with climate change and reimagine themselves in turn. © 2011 John Wiley & Sons, Ltd.

Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

Abstract: Free radicals and other oxidants have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. The free radicals, both the reactive oxygen species (ROS) and reactive nitrogen species (RNS), are derived from both endogenous sources (mitochondria, peroxisomes, endoplasmic reticulum, phagocytic cells etc.) and exogenous sources (pollution, alcohol, tobacco smoke, heavy metals, transition metals, industrial solvents, pesticides, certain drugs like halothane, paracetamol, and radiation). Free radicals can adversely affect various important classes of biological molecules such as nucleic acids, lipids, and proteins, thereby altering the normal redox status leading to increased oxidative stress. The free radicals induced oxidative stress has been reported to be involved in several diseased conditions such as diabetes mellitus, neurodegenerative disorders (Parkinson’s disease-PD, Alzheimer’s disease-AD and Multiple sclerosis-MS), cardiovascular diseases (atherosclerosis and hypertension), respiratory diseases (asthma), cataract development, rheumatoid arthritis and in various cancers (colorectal, prostate, breast, lung, bladder cancers). This review deals with chemistry, formation and sources, and molecular targets of free radicals and it provides a brief overview on the pathogenesis of various diseased conditions caused by ROS/RNS.

The ensemble nature of allostery

Abstract: Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.

Water Dispersion Interactions Strongly Influence Simulated Structural Properties of Disordered Protein States

Abstract: Many proteins can be partially or completely disordered under physiological conditions. Structural characterization of these disordered states using experimental methods can be challenging, since they are composed of a structurally heterogeneous ensemble of conformations rather than a single dominant conformation. Molecular dynamics (MD) simulations should in principle provide an ideal tool for elucidating the composition and behavior of disordered states at an atomic level of detail. Unfortunately, MD simulations using current physics-based models tend to produce disordered-state ensembles that are structurally too compact relative to experiments. We find that the water models typically used in MD simulations significantly underestimate London dispersion interactions, and speculate that this may be a possible reason for these erroneous results. To test this hypothesis, we create a new water model, TIP4P-D, that approximately corrects for these deficiencies in modeling water dispersion interactions while ...