scholarly journals Pseudo-DUBs as allosteric activators and molecular scaffolds of protein complexes

2018 ◽  
Vol 46 (2) ◽  
pp. 453-466 ◽  
Author(s):  
Miriam Walden ◽  
Safi Kani Masandi ◽  
Krzysztof Pawłowski ◽  
Elton Zeqiraj
Keyword(s):  
Cell Biology ◽  
Protein Complexes ◽  
Cell Signalling ◽  
Control Cell ◽  
Mechanisms Of Action ◽  
Molecular Scaffolds ◽  
Polyubiquitin Chains ◽  
Macromolecular Complexes ◽  
Cellular Life ◽  
Almost All

The ubiquitin (Ub) proteasome system and Ub signalling networks are crucial to cell biology and disease development. Deubiquitylases (DUBs) control cell signalling by removing mono-Ub and polyubiquitin chains from substrates. DUBs take part in almost all processes that regulate cellular life and are frequently dysregulated in disease. We have catalogued 99 currently known DUBs in the human genome and sequence conservation analyses of catalytic residues suggest that 11 lack enzyme activity and are classed as pseudo-DUBs. These pseudoenzymes play important biological roles by allosterically activating catalytically competent DUBs as well as other active enzymes. Additionally, pseudoenzymes act as assembly scaffolds of macromolecular complexes. We discuss how pseudo-DUBs have lost their catalytic activity, their diverse mechanisms of action and their potential as therapeutic targets. Many known pseudo-DUBs play crucial roles in cell biology and it is likely that unstudied and overlooked pseudo-DUB genes will have equally important functions.

scholarly journals Cytosolic delivery of large supramolecular protein complexes arranged on DNA nanopegboards

2017 ◽  
Author(s):  
Pavel M. Nikolov ◽  
Katja J. Koßmann ◽  
Alessa Schilling ◽  
Alessandro Angelin ◽  
Josipa Brglez ◽  
...  
Keyword(s):  
Cell Biology ◽  
Glucose Sensor ◽  
Protein Complexes ◽  
Cell Signalling ◽  
Model Systems ◽  
Dna Nanostructures ◽  
Multifunctional Protein ◽  
Multiprotein Complexes ◽  
Intracellular Targeting ◽  
Cytosolic Delivery

AbstractA generic methodology for cytosolic delivery of large supramolecular multiprotein complexes into living cells is described that takes advantage of the highly-controllable bottom-up fabrication of protein-decorated DNA nanostructures and the microfluidic “cell squeezing” technique. Therein, cells are deformed upon passage through a narrow constriction leading to formation of transient holes in the cell membrane that enable the diffusion of the protein-DNA nanostructures from the surrounding buffer into the cytosol. A diverse set of multiprotein complexes was assembled on DNA origami nanostructures using streptavidin and the sensitive glucose sensor protein FLIP as model systems. We demonstrate that our approach allows for the direct cytosolic delivery of these multifunctional protein complexes into the cytosol of HeLa cells. We also demonstrate that targeting groups can be incorporated into the protein-DNA nanoassemblies to enable their intracellular targeting to cytosolic compartments, such as the cytoskeleton or nucleus. We believe that this methodology will open up novel strategies for research in fundamental cell biology, such as the reverseengineering of the supramolecular machinery involved in gene regulation, cell signalling, or cell division. Furthermore, direct applications in immunotherapy can be foreseen.

The role of ESCRT proteins in attenuation of cell signalling

2009 ◽  
Vol 37 (1) ◽  
pp. 137-142 ◽  
Author(s):  
Lina M. Rodahl ◽  
Susanne Stuffers ◽  
Viola H. Lobert ◽  
Harald Stenmark
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Membrane Proteins ◽  
Protein Complexes ◽  
Cell Signalling ◽  
Control Cell ◽  
Endosomal Sorting ◽  
Tumour Suppression ◽  
Multivesicular Endosomes

The ESCRT (endosomal sorting complex required for transport) machinery consists of four protein complexes that mediate sorting of ubiquitinated membrane proteins into the intraluminal vesicles of multivesicular endosomes, thereby targeting them for degradation in lysosomes. In the present paper, we review how ESCRT-mediated receptor down-regulation affects signalling downstream of Notch and growth factor receptors, and how ESCRTs may control cell proliferation, survival and cytoskeletal functions and contribute to tumour suppression.

Biophysics (and sociology) of ceramides.

2005 ◽  
Vol 72 ◽  
pp. 177-188 ◽  
Author(s):  
Félix M. Goñi ◽  
F-Xabier Contreras ◽  
L-Ruth Montes ◽  
Jesús Sot ◽  
Alicia Alonso
Keyword(s):  
Cell Biology ◽  
Positive Curvature ◽  
Acyl Chain ◽  
Cell Signalling ◽  
Hexagonal Structure ◽  
Lipid Monolayer ◽  
Flip Flop ◽  
Long Chain ◽  
Bilayer Permeability

In the past decade, the long-neglected ceramides (N-acylsphingosines) have become one of the most attractive lipid molecules in molecular cell biology, because of their involvement in essential structures (stratum corneum) and processes (cell signalling). Most natural ceramides have a long (16-24 C atoms) N-acyl chain, but short N-acyl chain ceramides (two to six C atoms) also exist in Nature, apart from being extensively used in experimentation, because they can be dispersed easily in water. Long-chain ceramides are among the most hydrophobic molecules in Nature, they are totally insoluble in water and they hardly mix with phospholipids in membranes, giving rise to ceramide-enriched domains. In situ enzymic generation, or external addition, of long-chain ceramides in membranes has at least three important effects: (i) the lipid monolayer tendency to adopt a negative curvature, e.g. through a transition to an inverted hexagonal structure, is increased, (ii) bilayer permeability to aqueous solutes is notoriously enhanced, and (iii) transbilayer (flip-flop) lipid motion is promoted. Short-chain ceramides mix much better with phospholipids, promote a positive curvature in lipid monolayers, and their capacities to increase bilayer permeability or transbilayer motion are very low or non-existent.

scholarly journals A particle size threshold governs diffusion and segregation of PAR-3 during cell polarization

2021 ◽  
Author(s):  
Yiran Chang ◽  
Danie J Dickinson
Keyword(s):  
Cell Biology ◽  
Protein Complexes ◽  
Quantitative Model ◽  
Cell Polarization ◽  
Protein Distribution ◽  
Cell Stage ◽  
Viscous Forces ◽  
Dependent Protein ◽  
Regulate Protein ◽  
Size Threshold

Regulation of subcellular components' localization and motion is a critical theme in cell biology. Cells use the actomyosin cortex to regulate protein distribution on the plasma membrane, but the interplay between membrane binding, cortical movements and protein distribution remains poorly understood. In a polarizing one-cell stage Caenorhabditis elegans embryo, actomyosin flows transport PAR protein complexes into an anterior cortical domain to establish the anterior-posterior axis of the animal. Oligomerization of a key scaffold protein, PAR-3, is required for aPAR cortical localization and segregation. Although PAR-3 oligomerization is essential for polarization, it remains unclear how oligomer size contributes to aPAR segregation because PAR-3 oligomers are a heterogeneous population of many different sizes. To address this question, we engineered PAR-3 to defined sizes. We report that PAR-3 trimers are necessary and sufficient for PAR-3 function during polarization and later embryo development, while larger PAR-3 clusters are dispensable. Quantitative analysis of PAR-3 diffusion showed that PAR-3 clusters larger than a trimer are transported by viscous forces without being physically captured by the actomyosin cortex. Our study provides a quantitative model for size-dependent protein transportation of membrane proteins by cortical flow.

scholarly journals Phylogeny-Guided Selection of Priority Groups for Venom Bioprospecting: Harvesting Toxin Sequences in Tarantulas as a Case Study

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 488 ◽  
Author(s):  
Tim Lüddecke ◽  
Andreas Vilcinskas ◽  
Sarah Lemke
Keyword(s):  
Success Rate ◽  
Mechanisms Of Action ◽  
Rational Selection ◽  
Almost All ◽  
Novel Drug ◽  
Drug Leads ◽  
Novel Structures ◽  
Animal Venoms ◽  
Selection Of

Animal venoms are promising sources of novel drug leads, but their translational potential is hampered by the low success rate of earlier biodiscovery programs, in part reflecting the narrow selection of targets for investigation. To increase the number of lead candidates, here we discuss a phylogeny-guided approach for the rational selection of venomous taxa, using tarantulas (family Theraphosidae) as a case study. We found that previous biodiscovery programs have prioritized the three subfamilies Ornithoctoninae, Selenocosmiinae, and Theraphosinae, which provide almost all of the toxin sequences currently available in public databases. The remaining subfamilies are poorly represented, if at all. These overlooked subfamilies include several that form entire clades of the theraphosid life tree, such as the subfamilies Eumenophorinae, Harpactirinae, and Stromatopelminae, indicating that biodiversity space has not been covered effectively for venom biodiscovery in Theraphosidae. Focusing on these underrepresented taxa will increase the likelihood that promising candidates with novel structures and mechanisms of action can be identified in future bioprospecting programs.

How the sperm triggers development of the egg: what have we learned and what can we expect in the next millennium?

Zygote ◽  
1999 ◽  
Vol 8 (S1) ◽  
pp. S7-S8
Author(s):  
David Epel
Keyword(s):  
Sea Urchin ◽  
Cell Biology ◽  
Control Cell ◽  
Rapid Evolution ◽  
Cell Activity ◽  
Turn Of The Century ◽  
Direct Demonstration ◽  
Creative Research ◽  
Contemporary Work ◽  
Species Specific

The problem of how the sperm activates the egg has captivated the attention of cell and developmental biologists since the turn of the century. An early focus concerned species-specific fertilisation and the pioneering work of Lilly and Tyler (Tyler & Tyler, 1966) used immunological analogies to provide explanations of species-specific fertilisation. Contemporary work has focused on the identity of unique receptors on the sperm and the egg as exemplified in the work of Lennarz (Ohlendieck & Lennarz, 1996), Vacquier (Vacquier, et al., 1995) and Wasserman (1999). Lately, this approach has provided unexpected insights on how speciation might occur. Speciation requires reproductive isolation and creative research from the Vacquier laboratory has demonstrated how reproductive barriers might occur through rapid evolution of sperm/egg recognition systems (Lee et al., 1995).Studies on the cell biology of activation received a major impetus in the 1930s with Mazia's observation of a calcium increase in eggs of the sea urchin following fertilisation (Mazia, 1937). His discovery, however, was a premature one in that there was no satisfactory model at that time for explaining how a calcium increase could affect cell activity. It took almost 40 years to develop a paradigm, and this came from studies on muscle and nerve which revealed how calcium increases could somehow control cell activity. Work in the 1970s rapidly established a similar role for calcium in activation of the egg at fertilisation. The first break-through was the direct demonstration by Steinhardt & Epel (1974) that calcium was involved in egg activation, through manipulation of calcium levels in sea urchin oocytes by use of calcium ionophores.

scholarly journals Bioelectrical understanding and engineering of cell biology

2020 ◽  
Vol 17 (166) ◽  
pp. 20200013 ◽  
Author(s):  
Zoe Schofield ◽  
Gabriel N. Meloni ◽  
Peter Tran ◽  
Christian Zerfass ◽  
Giovanni Sena ◽  
...  
Keyword(s):  
Systems Biology ◽  
Cell Biology ◽  
Genetic Basis ◽  
Control Cell ◽  
Status Quo ◽  
Cell Behaviour ◽  
Cellular Processes ◽  
Mechanical Responses ◽  
Predictive Understanding ◽  
Biology Research

The last five decades of molecular and systems biology research have provided unprecedented insights into the molecular and genetic basis of many cellular processes. Despite these insights, however, it is arguable that there is still only limited predictive understanding of cell behaviours. In particular, the basis of heterogeneity in single-cell behaviour and the initiation of many different metabolic, transcriptional or mechanical responses to environmental stimuli remain largely unexplained. To go beyond the status quo , the understanding of cell behaviours emerging from molecular genetics must be complemented with physical and physiological ones, focusing on the intracellular and extracellular conditions within and around cells. Here, we argue that such a combination of genetics, physics and physiology can be grounded on a bioelectrical conceptualization of cells. We motivate the reasoning behind such a proposal and describe examples where a bioelectrical view has been shown to, or can, provide predictive biological understanding. In addition, we discuss how this view opens up novel ways to control cell behaviours by electrical and electrochemical means, setting the stage for the emergence of bioelectrical engineering.

scholarly journals Insulin signalling: putting the G- in protein-protein interactions

2004 ◽  
Vol 380 (1) ◽  
pp. e11-e12 ◽  
Author(s):  
Craig C. MALBON
Keyword(s):  
Insulin Receptor ◽  
Cross Talk ◽  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Cell Biology ◽  
Receptor Tyrosine Kinases ◽  
Insulin Signalling ◽  
Cell Signalling ◽  
Protein Protein Interactions ◽  
Proximal Point

Cell signalling via receptor tyrosine kinases, such as the insulin receptor, and via heterotrimeric G-proteins, such as Gαi, Gαs and Gαq family members, constitute two of most avidly studied paradigms in cell biology. That elements of these two populous signalling pathways must cross-talk to achieve proper signalling in the regulation of cell proliferation, differentiation and metabolism has been anticipated, but the evolution of our thinking and the analysis of such cross-talk have lagged behind the ever-expanding troupe of players and the recognition of multivalency as the rule, rather than the exception, in signalling biology. New insights have been provided by Kreuzer et al. in this issue of the Biochemical Journal, in which insulin is shown to provoke recruitment of Gαi-proteins to insulin-receptor-based complexes that can regulate the gain of insulin-receptor-catalysed autophosphorylation, a proximal point in the insulin-sensitive cascade of signalling. Understanding the convergence and cross-talk of signals from the receptor tyrosine kinases and G-protein-coupled receptor pathways in physical, spatial and temporal contexts will remain a major challenge of cell biology.

scholarly journals The Scissors Model of Microcrack Detection in Bone: Work in Progress

2010 ◽  
Vol 1274 ◽  
Author(s):  
David Taylor ◽  
Lauren Mulcahy ◽  
Gerardo Presbitero ◽  
Pietro Tisbo ◽  
Clodagh Dooley ◽  
...  
Keyword(s):  
Cell Biology ◽  
Cell Signalling ◽  
System Modelling ◽  
Ongoing Research ◽  
Cellular Processes ◽  
Disease States ◽  
Bone Damage ◽  
Model Cell ◽  
Drug Treatments ◽  
Microcrack Detection

AbstractWe have proposed a new model for microcrack detection by osteocytes in bone. According to this model, cell signalling is initiated by the cutting of cellular processes which span the crack. We show that shear displacements of the crack faces are needed to rupture these processes, in an action similar to that of a pair of scissors. Current work involves a combination of cell biology experiments, theoretical and experimental fracture mechanics and system modelling using control theory approaches. The approach will be useful for understanding effects of extreme loading, aging, disease states and drug treatments on bone damage and repair; the present paper presents recent results from experiments and simulations as part of current, ongoing research.

Salmonella in Australia: understanding and controlling infection

2017 ◽  
Vol 38 (3) ◽  
pp. 112
Author(s):  
Joshua PM Newson
Keyword(s):  
Host Cell ◽  
Cell Biology ◽  
Protein Translocation ◽  
Cell Signalling ◽  
Effector Proteins ◽  
Host Cells ◽  
Secretion Systems ◽  
Significant Burden ◽  
Systemic Infections ◽  
Bacterial Effectors

The bacterium Salmonella causes a spectrum of foodborne diseases ranging from acute gastroenteritis to systemic infections, and represents a significant burden of disease globally. In Australia, Salmonella is frequently associated with outbreaks and is a leading cause of foodborne illness, which results in a significant medical and economic burden. Salmonella infection involves colonisation of the small intestine, where the bacteria invades host cells and establishes an intracellular infection. To survive within host cells, Salmonella employs type-three secretion systems to deliver bacterial effector proteins into the cytoplasm of host cells. These bacterial effectors seek out and modify specific host proteins, disrupting host processes such as cell signalling, intracellular trafficking, and programmed cell death. This strategy of impairing host cells allows Salmonella to establish a replicative niche within the cell, where they can replicate to high numbers before escaping to infect neighbouring cells, or be transmitted to new hosts. While the importance of effector protein translocation to infection is well established, our understanding of many effector proteins remains incomplete. Many Salmonella effectors have unknown function and unknown roles during infection. A greater understanding of how Salmonella manipulates host cells during infection will lead to improved strategies to prevent, control, and eliminate disease. Further, studying effector proteins can be a useful means for exploring host cell biology and elucidating the details of host cell signalling.

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