scholarly journals Emergence and Enhancement of Ultrasensitivity through Posttranslational Modulation of Protein Stability

2021 ◽  
Author(s):  
Carla Kumbale ◽  
Eberhard Voit ◽  
Qiang Zhang
Keyword(s):  
Posttranslational Modification ◽  
Signal Amplification ◽  
Covalent Modification ◽  
Zero Order ◽  
Protein Stabilization ◽  
Signaling Proteins ◽  
Cellular Functions ◽  
Protein Substrate ◽  
Protein Substrates ◽  
Inducible Protein

Signal amplification converts a linear input to a steeply sigmoid output and is central to cellular functions. One canonical signal amplifying motif is zero-order ultrasensitivity through the posttranslational modification (PTM) cycle signaling proteins. The functionality of this signaling motif has been examined conventionally by supposing that the total amount of the protein substrates remains constant. However, covalent modification of signaling proteins often results in changes in their stability, which affects the abundance of the protein substrates. Here we use a mathematical model to explore the signal amplification properties in such scenarios. Our simulations indicate that PTM-induced protein stabilization brings the enzymes closer to saturation, and as a result, ultrasensitivity may emerge or is greatly enhanced, with a steeper sigmoidal response of higher magnitude and generally longer response time. In cases where PTM destabilizes the protein, ultrasensitivity can be regained through changes in the activities of the involved enzymes or from increased protein synthesis. Interestingly, ultrasensitivity is not limited to modified or unmodified protein substrates; the total protein substrate can also exhibit ultrasensitivity. It is conceivable that cells use inducible protein stabilization as a way to boost signal amplification while saving energy by keeping the protein substrate at low basal conditions.

scholarly journals Emergence and Enhancement of Ultrasensitivity through Posttranslational Modulation of Protein Stability

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1741
Author(s):  
Carla M. Kumbale ◽  
Eberhard O. Voit ◽  
Qiang Zhang
Keyword(s):  
Signal Amplification ◽  
Biological Rhythms ◽  
Covalent Modification ◽  
Protein Stabilization ◽  
Enzymatic Reactions ◽  
Signaling Proteins ◽  
Protein Substrate ◽  
Free Protein ◽  
Protein Substrates ◽  
Inducible Protein

Signal amplification in biomolecular networks converts a linear input to a steeply sigmoid output and is central to a number of cellular functions including proliferation, differentiation, homeostasis, adaptation, and biological rhythms. One canonical signal amplifying motif is zero-order ultrasensitivity that is mediated through the posttranslational modification (PTM) cycle of signaling proteins. The functionality of this signaling motif has been examined conventionally by supposing that the total amount of the protein substrates remains constant, as by the classical Koshland–Goldbeter model. However, covalent modification of signaling proteins often results in changes in their stability, which affects the abundance of the protein substrates. Here, we use mathematical models to explore the signal amplification properties in such scenarios and report some novel aspects. Our analyses indicate that PTM-induced protein stabilization brings the enzymes closer to saturation. As a result, ultrasensitivity may emerge or is greatly enhanced, with a steeper sigmoidal response, higher magnitude, and generally longer response time. In cases where PTM destabilizes the protein, ultrasensitivity can be regained through changes in the activities of the involved enzymes or from increased protein synthesis. Importantly, ultrasensitivity is not limited to modified or unmodified protein substrates—when protein turnover is considered, the total free protein substrate can also exhibit ultrasensitivity under several conditions. When full enzymatic reactions are used instead of Michaelis–Menten kinetics for the modeling, the total free protein substrate can even exhibit nonmonotonic dose–response patterns. It is conceivable that cells use inducible protein stabilization as a strategy in the signaling network to boost signal amplification while saving energy by keeping the protein substrate levels low at basal conditions.

Regulation of the water channel aquaporin-2 by posttranslational modification

2011 ◽  
Vol 300 (5) ◽  
pp. F1062-F1073 ◽  
Author(s):  
Hanne B. Moeller ◽  
Emma T. B. Olesen ◽  
Robert A. Fenton
Keyword(s):  
Membrane Proteins ◽  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Posttranslational Modification ◽  
Water Channel ◽  
Cellular Functions ◽  
Aquaporin 2 ◽  
Eukaryotic Membrane Proteins ◽  
Insight Into

The cellular functions of many eukaryotic membrane proteins, including the vasopressin-regulated water channel aquaporin-2 (AQP2), are regulated by posttranslational modifications. In this article, we discuss the experimental discoveries that have advanced our understanding of how posttranslational modifications affect AQP2 function, especially as they relate to the role of AQP2 in the kidney. We review the most recent data demonstrating that glycosylation and, in particular, phosphorylation and ubiquitination are mechanisms that regulate AQP2 activity, subcellular sorting and distribution, degradation, and protein interactions. From a clinical perspective, posttranslational modification resulting in protein misrouting or degradation may explain certain forms of nephrogenic diabetes insipidus. In addition to providing major insight into the function and dynamics of renal AQP2 regulation, the analysis of AQP2 posttranslational modification may provide general clues as to the role of posttranslational modification for regulation of other membrane proteins.

scholarly journals Structure and Lateral Organization of Phosphatidylinositol 4,5-bisphosphate

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3885
Author(s):  
Luís Borges-Araújo ◽  
Fabio Fernandes
Keyword(s):  
Membrane Dynamics ◽  
Eukaryotic Cells ◽  
Signaling Proteins ◽  
Steady State Concentration ◽  
Biophysical Properties ◽  
Cellular Functions ◽  
Downstream Signaling ◽  
A Minor ◽  
State Concentration ◽  
Lateral Organization

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a minor but ubiquitous component of the inner leaflet of the plasma membrane of eukaryotic cells. However, due to its particular complex biophysical properties, it stands out from its neighboring lipids as one of the most important regulators of membrane-associated signaling events. Despite its very low steady-state concentration, PI(4,5)P2 is able to engage in a multitude of simultaneous cellular functions that are temporally and spatially regulated through the presence of localized transient pools of PI(4,5)P2 in the membrane. These pools are crucial for the recruitment, activation, and organization of signaling proteins and consequent regulation of downstream signaling. The present review showcases some of the most important PI(4,5)P2 molecular and biophysical properties as well as their impact on its membrane dynamics, lateral organization, and interactions with other biochemical partners.

scholarly journals SUMOylation of human septins is critical for septin filament bundling and cytokinesis

2017 ◽  
Vol 216 (12) ◽  
pp. 4041-4052 ◽  
Author(s):  
David Ribet ◽  
Serena Boscaini ◽  
Clothilde Cauvin ◽  
Martin Siguier ◽  
Serge Mostowy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Posttranslational Modification ◽  
Diffusion Barriers ◽  
Cytoskeletal Proteins ◽  
Cellular Functions ◽  
Terminal Domain ◽  
Subcellular Compartmentalization ◽  
Protein Recruitment ◽  
Septin Filament

Septins are cytoskeletal proteins that assemble into nonpolar filaments. They are critical in diverse cellular functions, acting as scaffolds for protein recruitment and as diffusion barriers for subcellular compartmentalization. Human septins are encoded by 13 different genes and are classified into four groups based on sequence homology (SEPT2, SEPT3, SEPT6, and SEPT7 groups). In yeast, septins were among the first proteins reported to be modified by SUMOylation, a ubiquitin-like posttranslational modification. However, whether human septins could be modified by small ubiquitin-like modifiers (SUMOs) and what roles this modification may have in septin function remains unknown. In this study, we first show that septins from all four human septin groups can be covalently modified by SUMOs. We show in particular that endogenous SEPT7 is constitutively SUMOylated during the cell cycle. We then map SUMOylation sites to the C-terminal domain of septins belonging to the SEPT6 and SEPT7 groups and to the N-terminal domain of septins from the SEPT3 group. We finally demonstrate that expression of non-SUMOylatable septin variants from the SEPT6 and SEPT7 groups leads to aberrant septin bundle formation and defects in cytokinesis after furrow ingression. Altogether, our results demonstrate a pivotal role for SUMOylation in septin filament bundling and cell division.

scholarly journals Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
James Bowman ◽  
Mary A. Rodgers ◽  
Mude Shi ◽  
Rina Amatya ◽  
Bruce Hostager ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Posttranslational Modification ◽  
Bacterial Infections ◽  
Covalent Modification ◽  
Bacterial Lipopolysaccharide ◽  
Toll Like Receptor ◽  
Microbial Infection ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Chain ◽  
Immune Signaling

ABSTRACT Linear ubiquitination is an atypical posttranslational modification catalyzed by the linear-ubiquitin-chain assembly complex (LUBAC), containing HOIP, HOIL-1L, and Sharpin. LUBAC facilitates NF-κB activation and inflammation upon receptor stimulation by ligating linear ubiquitin chains to critical signaling molecules. Indeed, linear-ubiquitination-dependent signaling is essential to prevent pyogenic bacterial infections that can lead to death. While linear ubiquitination is essential for intracellular receptor signaling upon microbial infection, this response must be measured and stopped to avoid tissue damage and autoimmunity. While LUBAC is activated upon bacterial stimulation, the mechanisms regulating LUBAC activity in response to bacterial stimuli have remained elusive. We demonstrate that LUBAC activity itself is downregulated through ubiquitination, specifically, ubiquitination of the catalytic subunit HOIP at the carboxyl-terminal lysine 1056. Ubiquitination of Lys1056 dynamically altered HOIP conformation, resulting in the suppression of its catalytic activity. Consequently, HOIP Lys1056-to-Arg mutation led not only to persistent LUBAC activity but also to prolonged NF-κB activation induced by bacterial lipopolysaccharide-mediated Toll-like receptor 4 (TLR4) stimulation, whereas it showed no effect on NF-κB activation induced by CD40 stimulation. This study describes a novel posttranslational regulation of LUBAC-mediated linear ubiquitination that is critical for specifically directing TLR4-mediated NF-κB activation. IMPORTANCE Posttranslational modification of proteins enables cells to respond quickly to infections and immune stimuli in a tightly controlled manner. Specifically, covalent modification of proteins with the small protein ubiquitin is essential for cells to initiate and terminate immune signaling in response to bacterial and viral infection. This process is controlled by ubiquitin ligase enzymes, which themselves must be regulated to prevent persistent and deleterious immune signaling. However, how this regulation is achieved is poorly understood. This paper reports a novel ubiquitination event of the atypical ubiquitin ligase HOIP that is required to terminate bacterial lipopolysaccharide (LPS)-induced TLR4 immune signaling. Ubiquitination causes the HOIP ligase to undergo a conformational change, which blocks its enzymatic activity and ultimately terminates LPS-induced TLR4 signaling. These findings provide a new mechanism for controlling HOIP ligase activity that is vital to properly regulate a proinflammatory immune response.

scholarly journals A promiscuous inflammasome sparks replication of a common tumor virus

2020 ◽  
Vol 117 (3) ◽  
pp. 1722-1730 ◽  
Author(s):  
Eric M. Burton ◽  
Raphaela Goldbach-Mansky ◽  
Sumita Bhaduri-McIntosh
Keyword(s):  
Nlrp3 Inflammasome ◽  
Posttranslational Modification ◽  
Epstein Barr Virus ◽  
Inflammatory Responses ◽  
Cellular Functions ◽  
Barr Virus ◽  
Neonatal Onset ◽  
Lytic Reactivation ◽  
Tumor Virus ◽  
Epstein Barr

Viruses activate inflammasomes but then subvert resulting inflammatory responses to avoid elimination. We asked whether viruses could instead use such activated or primed inflammasomes to directly aid their propagation and spread. Since herpesviruses are experts at coopting cellular functions, we investigated whether Epstein−Barr virus (EBV), an oncoherpesvirus, exploits inflammasomes to activate its replicative or lytic phase. Indeed, our experiments reveal that EBV exploits several inflammasome sensors to actually activate its replicative phase from quiescence/latency. In particular, TXNIP, a key inflammasome intermediary, causes assembly of the NLRP3 inflammasome, resulting in caspase-1−mediated depletion of the heterochromatin-inducing epigenetic repressor KAP1/TRIM28 in a subpopulation of cells. As a result, only TXNIPhiKAP1lo cells, that is, in a primed/prolytic state, turn expression of the replication/lytic/reactivation switch protein on to enter the replicative phase. Our findings 1) demonstrate that EBV dovetails its escape strategy to a key cellular danger-sensing mechanism, 2) indicate that transcription may be regulated by KAP1 abundance aside from canonical regulation through its posttranslational modification, 3) mechanistically link diabetes, which frequently activates the NLRP3 inflammasome, to deregulation of a tumor virus, and 4) demonstrate that B lymphocytes from NOMID (neonatal onset multisystem inflammatory disease) patients who have NLRP3 mutations and suffer from hyperactive innate responses are defective in controlling a herpesvirus.

scholarly journals Integrin-linked kinase (ILK) and its interactors

2001 ◽  
Vol 155 (4) ◽  
pp. 505-510 ◽  
Author(s):  
Chuanyue Wu ◽  
Shoukat Dedhar
Keyword(s):  
Cell Biology ◽  
Cell Shape ◽  
Shape Change ◽  
Signaling Proteins ◽  
Cellular Functions ◽  
Genetic Studies ◽  
Contact Sites ◽  
Cell Shape Change ◽  
Cell Matrix ◽  
Integrin Linked Kinase

How intracellular cytoskeletal and signaling proteins connect and communicate with the extracellular matrix (ECM) is a fundamental question in cell biology. Recent biochemical, cell biological, and genetic studies have revealed important roles of cytoplasmic integrin-linked kinase (ILK) and its interactive proteins in these processes. Cell adhesion to ECM is an important process that controls cell shape change, migration, proliferation, survival, and differentiation. Upon adhesion to ECM, integrins and a selective group of cytoskeletal and signaling proteins are recruited to cell matrix contact sites where they link the actin cytoskeleton to the ECM and mediate signal transduction between the intracellular and extracellular compartments. In this review, we discuss the molecular activities and cellular functions of ILK, a protein that is emerging as a key component of the cell–ECM adhesion structures.

scholarly journals Characteristics of polyamine stimulation of cyclic nucleotide-independent protein kinase reactions

1985 ◽  
Vol 232 (3) ◽  
pp. 767-771 ◽  
Author(s):  
K Ahmed ◽  
S A Goueli ◽  
H G Williams-Ashman
Keyword(s):  
Catalytic Activity ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Nuclear Protein ◽  
Direct Stimulation ◽  
Protein Substrate ◽  
Protein Substrates ◽  
Effects Of Temperature ◽  
Independent Protein ◽  
Stimulation Of

The extent of direct stimulation by spermine of reactions catalysed by nuclear N1 and N2 protein kinases purified from liver and prostate depends critically on the nature of the protein substrate. The chemically inert Co(NH3)36+ ion exerts effects on protein kinase reactions similar to those of spermidine or spermine. This enhancement of the phosphorylation of various protein substrates by polyamines or Co(NH3)63+ by purified nuclear protein kinase preparations was studied in relation to effects of temperature, pH and other factors. The results provide further support for our hypothesis [Ahmed, Wilson, Goueli & Williams-Ashman (1978) Biochem. J. 176, 739-750] that the enhancement of certain protein kinase reactions by polycations relates primarily to their interaction with the protein substrate, yielding more favourable conformations for phosphorylation by the protein kinase, rather than a direct effect on its catalytic activity.

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