scholarly journals Intein Inhibitors as Novel Antimicrobials: Protein Splicing in Human Pathogens, Screening Methods, and Off-Target Considerations

2021 ◽  
Vol 8 ◽  
Author(s):  
Diana A. Wall ◽  
Seanan P. Tarrant ◽  
Chunyu Wang ◽  
Kenneth V. Mills ◽  
Christopher W. Lennon
Keyword(s):  
Hedgehog Signaling ◽  
Structure And Function ◽  
Screening Methods ◽  
Protein Splicing ◽  
Proof Of Concept ◽  
Human Pathogens ◽  
Microbial World ◽  
Essential Proteins ◽  
And Function ◽  
Translational Process

Protein splicing is a post-translational process by which an intervening polypeptide, or intein, catalyzes its own removal from the flanking polypeptides, or exteins, concomitant with extein ligation. Although inteins are highly abundant in the microbial world, including within several human pathogens, they are absent in the genomes of metazoans. As protein splicing is required to permit function of essential proteins within pathogens, inteins represent attractive antimicrobial targets. Here we review key proteins interrupted by inteins in pathogenic mycobacteria and fungi, exciting discoveries that provide proof of concept that intein activity can be inhibited and that this inhibition has an effect on the host organism’s fitness, and bioanalytical methods that have been used to screen for intein activity. We also consider potential off-target inhibition of hedgehog signaling, given the similarity in structure and function of inteins and hedgehog autoprocessing domains.

scholarly journals Meta!Blast: A Serious Game to Explore the Complexities of Structural and Metabolic Cell Biology

2010 ◽  
Author(s):  
Eve S. Wurtele ◽  
Diane C. Bassham ◽  
Julie Dickerson ◽  
David J. Kabala ◽  
William Schneller ◽  
...  
Keyword(s):  
Molecular Oxygen ◽  
Cell Biology ◽  
Cellular Structure ◽  
Electron Excitation ◽  
Structure And Function ◽  
Domain Expert ◽  
Proof Of Concept ◽  
Virtual Plant ◽  
And Function ◽  
Virtual Interactive

Knowledge of cellular structure and function has increased dramatically with the advent of modern molecular and computational technologies. Helping students to understand cellular dynamics is a major challenge to educators. To address this challenge, we have developed the Kabala Engine, an open source engine based on OpenSG (http://www.opensg.org) and VRJuggler (http://www.vrjuggler.org). This engine is designed to enable biologists, and indeed any domain expert — chemists, artists, psychologists — to create virtual interactive worlds for teaching or research. As a proof-of-concept, we have used this engine to create Meta!Blast, a virtual plant cell containing a prototype chloroplast in which students can enter, activate the light reactions, including electron excitation, and create molecular oxygen and ATP.

scholarly journals Rer1p maintains ciliary length and signaling by regulating γ-secretase activity and Foxj1a levels

2013 ◽  
Vol 200 (6) ◽  
pp. 709-720 ◽  
Author(s):  
Nathalie Jurisch-Yaksi ◽  
Applonia J. Rose ◽  
Huiqi Lu ◽  
Tim Raemaekers ◽  
Sebastian Munck ◽  
...  
Keyword(s):  
Quality Control ◽  
Mammalian Cells ◽  
Hedgehog Signaling ◽  
Protein Quality ◽  
Structure And Function ◽  
Sensory Function ◽  
Secretase Activity ◽  
Cilia Formation ◽  
Left Right Asymmetry ◽  
And Function

Cilia project from the surface of most vertebrate cells and are important for several physiological and developmental processes. Ciliary defects are linked to a variety of human diseases, named ciliopathies, underscoring the importance of understanding signaling pathways involved in cilia formation and maintenance. In this paper, we identified Rer1p as the first endoplasmic reticulum/cis-Golgi–localized membrane protein involved in ciliogenesis. Rer1p, a protein quality control receptor, was highly expressed in zebrafish ciliated organs and regulated ciliary structure and function. Both in zebrafish and mammalian cells, loss of Rer1p resulted in the shortening of cilium and impairment of its motile or sensory function, which was reflected by hearing, vision, and left–right asymmetry defects as well as decreased Hedgehog signaling. We further demonstrate that Rer1p depletion reduced ciliary length and function by increasing γ-secretase complex assembly and activity and, consequently, enhancing Notch signaling as well as reducing Foxj1a expression.

scholarly journals Contribution of Crk Adaptor Proteins to Host Cell and Bacteria Interactions

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Narcisa Martinez-Quiles ◽  
Leigh Ann Feuerbacher ◽  
María Benito-León ◽  
Philip R. Hardwidge
Keyword(s):  
Escherichia Coli ◽  
Cell Adhesion ◽  
Host Cell ◽  
Adaptor Proteins ◽  
Structure And Function ◽  
Future Research ◽  
Human Pathogens ◽  
Wide Range ◽  
Alternatively Spliced ◽  
And Function

The Crk adaptor family of proteins comprises the alternatively spliced CrkI and CrkII isoforms, as well as the paralog Crk-like (CrkL) protein, which is encoded by a different gene. Initially thought to be involved in signaling during apoptosis and cell adhesion, this ubiquitously expressed family of proteins is now known to play essential roles in integrating signals from a wide range of stimuli. In this review, we describe the structure and function of the different Crk proteins. We then focus on the emerging roles of Crk adaptors during Enterobacteriaceae pathogenesis, with special emphasis on the important human pathogensSalmonella,Shigella,Yersinia, and enteropathogenicEscherichia coli. Throughout, we remark on opportunities for future research into this intriguing family of proteins.

scholarly journals Global homogenization of the structure and function in the soil microbiome of urban greenspaces

2021 ◽  
Vol 7 (28) ◽  
pp. eabg5809
Author(s):  
Manuel Delgado-Baquerizo ◽  
David J. Eldridge ◽  
Yu-Rong Liu ◽  
Blessing Sokoya ◽  
Jun-Tao Wang ◽  
...  
Keyword(s):  
Management Practices ◽  
Gene Diversity ◽  
Well Being ◽  
Structure And Function ◽  
Soil Microbiome ◽  
Human Populations ◽  
Human Pathogens ◽  
Natural Ecosystems ◽  
Urban Greenspaces ◽  
And Function

The structure and function of the soil microbiome of urban greenspaces remain largely undetermined. We conducted a global field survey in urban greenspaces and neighboring natural ecosystems across 56 cities from six continents, and found that urban soils are important hotspots for soil bacterial, protist and functional gene diversity, but support highly homogenized microbial communities worldwide. Urban greenspaces had a greater proportion of fast-growing bacteria, algae, amoebae, and fungal pathogens, but a lower proportion of ectomycorrhizal fungi than natural ecosystems. These urban ecosystems also showed higher proportions of genes associated with human pathogens, greenhouse gas emissions, faster nutrient cycling, and more intense abiotic stress than natural environments. City affluence, management practices, and climate were fundamental drivers of urban soil communities. Our work paves the way toward a more comprehensive global-scale perspective on urban greenspaces, which is integral to managing the health of these ecosystems and the well-being of human populations.

scholarly journals Author response: Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling

2013 ◽  
Author(s):  
Sigrid Nachtergaele ◽  
Daniel M Whalen ◽  
Laurel K Mydock ◽  
Zhonghua Zhao ◽  
Tomas Malinauskas ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Extracellular Domain ◽  
Structure And Function ◽  
Author Response ◽  
And Function

scholarly journals Structure and function of the Toscana virus cap-snatching endonuclease

2019 ◽  
Vol 47 (20) ◽  
pp. 10914-10930 ◽  
Author(s):  
Rhian Jones ◽  
Sana Lessoued ◽  
Kristina Meier ◽  
Stéphanie Devignot ◽  
Sergio Barata-García ◽  
...  
Keyword(s):  
Metal Ion ◽  
Rna Virus ◽  
Rift Valley Fever Virus ◽  
Substrate Binding ◽  
Functional Characterization ◽  
Structure And Function ◽  
Human Pathogens ◽  
Toscana Virus ◽  
Valley Fever ◽  
And Function

Abstract Toscana virus (TOSV) is an arthropod-borne human pathogen responsible for seasonal outbreaks of fever and meningoencephalitis in the Mediterranean basin. TOSV is a segmented negative-strand RNA virus (sNSV) that belongs to the genus phlebovirus (family Phenuiviridae, order Bunyavirales), encompassing other important human pathogens such as Rift Valley fever virus (RVFV). Here, we carried out a structural and functional characterization of the TOSV cap-snatching endonuclease, an N terminal domain of the viral polymerase (L protein) that provides capped 3′OH primers for transcription. We report TOSV endonuclease crystal structures in the apo form, in complex with a di-ketoacid inhibitor (DPBA) and in an intermediate state of inhibitor release, showing details on substrate binding and active site dynamics. The structure reveals substantial folding rearrangements absent in previously reported cap-snatching endonucleases. These include the relocation of the N terminus and the appearance of new structural motifs important for transcription and replication. The enzyme shows high activity rates comparable to other His+ cap-snatching endonucleases. Moreover, the activity is dependent on conserved residues involved in metal ion and substrate binding. Altogether, these results bring new light on the structure and function of cap-snatching endonucleases and pave the way for the development of specific and broad-spectrum antivirals.

Structure and function of neural networks in the retina

1988 ◽  
Vol 46 ◽  
pp. 26-27
Author(s):  
Peter Sterling
Keyword(s):  
Ganglion Cells ◽  
Three Dimensional ◽  
Structure And Function ◽  
Synaptic Connections ◽  
Visual Axis ◽  
One Dimensional ◽  
Cat Retina ◽  
Ultrathin Sections ◽  
And Function ◽  
Insight Into

The synaptic connections in cat retina that link photoreceptors to ganglion cells have been analyzed quantitatively. Our approach has been to prepare serial, ultrathin sections and photograph en montage at low magnification (˜2000X) in the electron microscope. Six series, 100-300 sections long, have been prepared over the last decade. They derive from different cats but always from the same region of retina, about one degree from the center of the visual axis. The material has been analyzed by reconstructing adjacent neurons in each array and then identifying systematically the synaptic connections between arrays. Most reconstructions were done manually by tracing the outlines of processes in successive sections onto acetate sheets aligned on a cartoonist's jig. The tracings were then digitized, stacked by computer, and printed with the hidden lines removed. The results have provided rather than the usual one-dimensional account of pathways, a three-dimensional account of circuits. From this has emerged insight into the functional architecture.

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