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"O'Neal, Claire"
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Structural Basis for the Activation of Cholera Toxin by Human ARF6-GTP
The Vibrio cholerae bacterium causes devastating diarrhea when it infects the human intestine. The key event is adenosine diphosphate (ADP)-ribosylation of the human signaling protein G[subscript S[alpha]], catalyzed by the cholera toxin A1 subunit (CTA1). This reaction is allosterically activated by human ADP-ribosylation factors (ARFs), a family of essential and ubiquitous G proteins. Crystal structures of a CTA1:ARF6-GTP (guanosine triphosphate) complex reveal that binding of the human activator elicits dramatic changes in CTA1 loop regions that allow nicotinamide adenine dinucleotide (NAD⁺) to bind to the active site. The extensive toxin:ARF-GTP interface surface mimics ARF-GTP recognition of normal cellular protein partners, which suggests that the toxin has evolved to exploit promiscuous binding properties of ARFs.
Journal Article
A project guide to volcanoes
Describes the geology behind different types of volcanoes with twelve science projects.
Book
Structural biology and structure-based inhibitor design of cholera toxin and heat-labile enterotoxin
Structural biology studies on cholera toxin and the closely related heat-labile enterotoxin from enterotoxigenic Escherichia coli over the past decade have shed light on the mechanism of toxin action at molecular and atomic levels. Also, components of the extracellular protein secretion apparatus that translocate the toxins across the outer membrane are being investigated. At the same time, structure-based design has led to various classes of compounds targeting different toxin sites, including highly potent multivalent inhibitors that block the toxin receptor-binding process.
Journal Article
A project guide to chemistry
From cars rusting to stomachs digesting, chemical reactions make things happen. These easy and fun projects on chemistry and chemical reactions will help you think like a chemist as you burn oxygen in air, move microscopic metals through solution, make your own plastic, and much more.
Book
Structural studies of the cholera toxin catalytic subunit
Vibrio cholerae causes devastating diarrhea when it infects the human intestine. The primary virulence factor for the disease is cholera toxin (CT), a heterohexameric protein toxin that ADP-ribosylates the human signaling protein GSα. To form the enzymatically active toxic fragment, pro-enzyme CT undergoes limited proteolysis and disulfide bond reduction. Reduction occurs in the ER via the reductase/chaperone protein disulfide isomerase (PDI), an interaction which is further explored in this work. Without a chaperone, activational modifications render CT unstable in solution, preventing a structural understanding of conformational changes resulting from toxin activation and substrate binding. Crystal structures of an A-subunit variant, Y30S, which requires no activational modifications for full activity, represent the first structures of active CT. Differences between CTY30S and wild-type, proenzyme CT are observed only in two A-subunit loop regions. The activation loop (residues 25-36) is disordered in CTY30S, while the active-site loop (residues 47-56) displays varying degrees of order, suggesting that activation loop disorder predisposes the active-site loop to be more flexible than in unactivated wild-type CT. A model shows how the activational modifications could be communicated to the active site. CTA1 is allosterically activated by interaction with human ADP-ribosylation factors (ARFs). Crystal structures of a CTA1:ARF6-GTP complex reveal that the extensive toxin:ARF-GTP interface mimics ARF-GTP recognition of normal cellular protein partners, suggesting that the toxin exploits promiscuous binding properties of ARFs. Upon binding the human protein activator, toxin activation is accomplished via dramatic conformational changes in CTA1 loop regions. The activation loop rearranges to contact ARF6-GTP as an amphipathic helix, which forces the active-site loop out of the active site. The new active-site loop position generates a possible GSα, binding surface, one which may only be available during interaction with ARF-GTP. Despite active-site accessibility in certain CTY30S crystal forms, soaking CTY30S crystals with massive concentrations of NAD+ resulted in poor quality and discontinuous maps of a fragment of an NAD+ molecule in the active site. However, crystals of the CTA1:ARF6-GTP complex soaked with the substrate yielded strong, continuous density that gives the first glimpse at the NAD+-binding mode of the toxin.
Dissertation
Ornette Coleman
Profiles the life and career of jazz saxophonist and father of free jazz Ornette Coleman.
Book
Localization of Secretory Mucins MUC5AC and MUC5B in Normal/Healthy Human Airways
Abstract
Rationale
MUC5AC and MUC5B are the predominant gel-forming mucins in the mucus layer of human airways. Each mucin has distinct functions and site-specific expression. However, the regional distribution of expression and cell types that secrete each mucin in normal/healthy human airways are not fully understood.
Objectives
To characterize the regional distribution of MUC5B and MUC5AC in normal/healthy human airways and assess which cell types produce these mucins, referenced to the club cell secretory protein (CCSP).
Methods
Multiple airway regions from 16 nonsmoker lungs without a history of lung disease were studied. MUC5AC, MUC5B, and CCSP expression/colocalization were assessed by RNA in situ hybridization and immunohistochemistry in five lungs with histologically healthy airways. Droplet digital PCR and cell cultures were performed for absolute quantification of MUC5AC/5B ratios and protein secretion, respectively.
Measurements and Main Results
Submucosal glands expressed MUC5B, but not MUC5AC. However, MUC5B was also extensively expressed in superficial epithelia throughout the airways except for the terminal bronchioles. Morphometric calculations revealed that the distal airway superficial epithelium was the predominant site for MUC5B expression, whereas MUC5AC expression was concentrated in proximal, cartilaginous airways. RNA in situ hybridization revealed MUC5AC and MUC5B were colocalized with CCSP-positive secretory cells in proximal superficial epithelia, whereas MUC5B and CCSP-copositive cells dominated distal regions.
Conclusions
In normal/healthy human airways, MUC5B is the dominant secretory mucin in the superficial epithelium and glands, with distal airways being a major site of expression. MUC5B and MUC5AC expression is a property of CCSP-positive secretory cells in superficial airway epithelia.
Journal Article
Airway Mucin Concentration as a Marker of Chronic Bronchitis
Chronic bronchitis is currently diagnosed by asking patients if they expectorate sputum on a regular basis. In this study, the concentration of mucin was higher in the induced sputum of patients with chronic bronchitis than in those who did not meet the case definition of the disorder.
Journal Article