Faculty Opinions recommendation of TRPV1 structures in distinct conformations reveal activation mechanisms.

2013 ◽  
Author(s):  
James K Stoops ◽  
Jun Liu
Keyword(s):  
Activation Mechanisms

scholarly journals Thiol-based switching mechanisms of stress-sensing chaperones

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Kathrin Ulrich ◽  
Blanche Schwappach ◽  
Ursula Jakob
Keyword(s):  
Oxidative Stress ◽  
Environmental Changes ◽  
Stress Conditions ◽  
Stress Exposure ◽  
Atp Levels ◽  
Protein Functions ◽  
Activation Mechanisms ◽  
Client Proteins ◽  
Stress Sensing ◽  
Redox Switches

AbstractThiol-based redox switches evolved as efficient post-translational regulatory mechanisms that enable individual proteins to rapidly respond to sudden environmental changes. While some protein functions need to be switched off to save resources and avoid potentially error-prone processes, protective functions become essential and need to be switched on. In this review, we focus on thiol-based activation mechanisms of stress-sensing chaperones. Upon stress exposure, these chaperones convert into high affinity binding platforms for unfolding proteins and protect cells against the accumulation of potentially toxic protein aggregates. Their chaperone activity is independent of ATP, a feature that becomes especially important under oxidative stress conditions, where cellular ATP levels drop and canonical ATP-dependent chaperones no longer operate. Vice versa, reductive inactivation and substrate release require the restoration of ATP levels, which ensures refolding of client proteins by ATP-dependent foldases. We will give an overview over the different strategies that cells evolved to rapidly increase the pool of ATP-independent chaperones upon oxidative stress and provide mechanistic insights into how stress conditions are used to convert abundant cellular proteins into ATP-independent holding chaperones.

scholarly journals Structure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhenfang Du ◽  
Benjamin P. Brown ◽  
Soyeon Kim ◽  
Donna Ferguson ◽  
Dean C. Pavlick ◽  
...  
Keyword(s):  
Tandem Duplication ◽  
Function Analysis ◽  
Treatment Strategies ◽  
Kinase Domain ◽  
Time Resolved ◽  
Egfr Activation ◽  
Domain Duplication ◽  
Activation Mechanisms ◽  
Potential Therapeutic Intervention ◽  
Egfr Kinase

AbstractMechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.

scholarly journals Species-Specific Regulation of TRPM2 by PI(4,5)P2 via the Membrane Interfacial Cavity

2021 ◽  
Vol 22 (9) ◽  
pp. 4637
Author(s):  
Daniel Barth ◽  
Andreas Lückhoff ◽  
Frank J. P. Kühn
Keyword(s):  
Amino Acid Residues ◽  
Hek 293 ◽  
Complete Inactivation ◽  
293 Cells ◽  
Activation Mechanisms ◽  
Specific Regulation ◽  
Species Specific ◽  
Inside Out ◽  
Positively Charged

The human apoptosis channel TRPM2 is stimulated by intracellular ADR-ribose and calcium. Recent studies show pronounced species-specific activation mechanisms. Our aim was to analyse the functional effect of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), commonly referred to as PIP2, on different TRPM2 orthologues. Moreover, we wished to identify the interaction site between TRPM2 and PIP2. We demonstrate a crucial role of PIP2, in the activation of TRPM2 orthologues of man, zebrafish, and sea anemone. Utilizing inside-out patch clamp recordings of HEK-293 cells transfected with TRPM2, differential effects of PIP2 that were dependent on the species variant became apparent. While depletion of PIP2 via polylysine uniformly caused complete inactivation of TRPM2, restoration of channel activity by artificial PIP2 differed widely. Human TRPM2 was the least sensitive species variant, making it the most susceptible one for regulation by changes in intramembranous PIP2 content. Furthermore, mutations of highly conserved positively charged amino acid residues in the membrane interfacial cavity reduced the PIP2 sensitivity in all three TRPM2 orthologues to varying degrees. We conclude that the membrane interfacial cavity acts as a uniform PIP2 binding site of TRPM2, facilitating channel activation in the presence of ADPR and Ca2+ in a species-specific manner.

scholarly journals Anti-NLRP3 Inflammasome Natural Compounds: An Update

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 136
Author(s):  
Baolong Liu ◽  
Jiujiu Yu
Keyword(s):  
Nlrp3 Inflammasome ◽  
Protein Complex ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Natural Compounds ◽  
Pyrin Domain ◽  
Inflammatory Protein ◽  
Wide Range ◽  
Activation Mechanisms ◽  
Stress Signals

The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex that recognizes various danger or stress signals from pathogens, the host, and the environment, leading to activation of caspase-1 and inducing inflammatory responses. This pro-inflammatory protein complex plays critical roles in pathogenesis of a wide range of diseases including neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Therefore, intensive efforts have been devoted to understanding its activation mechanisms and to searching for its specific inhibitors. Approximately forty natural compounds with anti-NLRP3 inflammasome properties have been identified. Here, we provide an update about new natural compounds that have been identified within the last three years to inhibit the NLRP3 inflammasome and offer an overview of the underlying molecular mechanisms of their anti-NLRP3 inflammasome activities.

scholarly journals Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E2 receptor EP2 subtype

2021 ◽  
Vol 7 (14) ◽  
pp. eabf1268
Author(s):  
Changxiu Qu ◽  
Chunyou Mao ◽  
Peng Xiao ◽  
Qingya Shen ◽  
Ya-Ni Zhong ◽  
...  
Keyword(s):  
G Protein ◽  
Rational Design ◽  
Receptor Activation ◽  
Prostaglandin E ◽  
Toggle Switch ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Ligand Selectivity ◽  
Activation Mechanisms ◽  
Prostaglandin E2 Receptor

Selective modulation of the heterotrimeric G protein α S subunit–coupled prostaglandin E2 (PGE2) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo–electron microscopy structure of the EP2-Gs complex with its endogenous agonist PGE2 and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W6.48 “toggle switch” and coupling to Gs via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE2 signaling system.

Activation mechanisms of sodium silicate-inhibited fluorite in flotation under neutral and slightly alkaline conditions

2021 ◽  
Vol 161 ◽  
pp. 106738
Author(s):  
Saizhen Jin ◽  
Leming Ou ◽  
Xiqi Ma ◽  
Hao Zhou ◽  
Zhengjun Zhang
Keyword(s):  
Sodium Silicate ◽  
Activation Mechanisms ◽  
Alkaline Conditions

scholarly journals Injectable Capsaicin for the Management of Pain Due to Osteoarthritis

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 778
Author(s):  
James N. Campbell ◽  
Randall Stevens ◽  
Peter Hanson ◽  
James Connolly ◽  
Diana S. Meske ◽  
...  
Keyword(s):  
Nervous System ◽  
Neuropathic Pain ◽  
Disruptive Effect ◽  
Single Administration ◽  
Trpv1 Channel ◽  
Therapeutic Benefits ◽  
Activation Mechanisms ◽  
Nociceptive Fibers ◽  
Potent Agonist ◽  
Topical Capsaicin

Capsaicin is a potent agonist of the TRPV1 channel, a transduction channel that is highly expressed in nociceptive fibers (pain fibers) throughout the peripheral nervous system. Given the importance of TRPV1 as one of several transduction channels in nociceptive fibers, much research has been focused on the potential therapeutic benefits of using TRPV1 antagonists for the management of pain. However, an antagonist has two limitations. First, an antagonist in principle generally only affects one receptor. Secondly, most antagonists must have an ongoing presence on the receptor to have an effect. Capsaicin overcomes both liabilities by disrupting peripheral terminals of nociceptive fibers that express TRPV1, and thereby affects all of the potential means of activating that pain fiber (not just TRPV1 function). This disruptive effect is dependent on the dose and can occur within minutes. Thus, unlike a typical receptor antagonist, continued bioavailability at the level of the receptor is not necessary. By disrupting the entire terminal of the TRPV1-expressing nociceptive fiber, capsaicin blocks all the activation mechanisms within that fiber, and not just TRPV1 function. Topical capsaicin, an FDA approved treatment for neuropathic pain, addresses pain from abnormal nociceptor activity in the superficial layers of the skin. Effects after a single administration are evident over a period of weeks to months, but in time are fully reversible. This review focuses on the rationale for using capsaicin by injection for painful conditions such as osteoarthritis (OA) and provides an update on studies completed to date.

scholarly journals Differential activation mechanisms of two isoforms of Gcr1 transcription factor generated from spliced and un-spliced transcripts in Saccharomyces cerevisiae

2020 ◽  
Author(s):  
Seungwoo Cha ◽  
Chang Pyo Hong ◽  
Hyun Ah Kang ◽  
Ji-Sook Hahn
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcription Factor ◽  
Target Genes ◽  
Gene Encoding ◽  
Metabolic Switch ◽  
Differential Activation ◽  
N Terminus ◽  
Activation Mechanisms ◽  
In Trans ◽  
Separate Activation

Abstract Gcr1, an important transcription factor for glycolytic genes in Saccharomyces cerevisiae, was recently revealed to have two isoforms, Gcr1U and Gcr1S, produced from un-spliced and spliced transcripts, respectively. In this study, by generating strains expressing only Gcr1U or Gcr1S using the CRISPR/Cas9 system, we elucidate differential activation mechanisms of these two isoforms. The Gcr1U monomer forms an active complex with its coactivator Gcr2 homodimer, whereas Gcr1S acts as a homodimer without Gcr2. The USS domain, 55 residues at the N-terminus existing only in Gcr1U, inhibits dimerization of Gcr1U and even acts in trans to inhibit Gcr1S dimerization. The Gcr1S monomer inhibits the metabolic switch from fermentation to respiration by directly binding to the ALD4 promoter, which can be restored by overexpression of the ALD4 gene, encoding a mitochondrial aldehyde dehydrogenase required for ethanol utilization. Gcr1U and Gcr1S regulate almost the same target genes, but show unique activities depending on growth phase, suggesting that these isoforms play differential roles through separate activation mechanisms depending on environmental conditions.

scholarly journals Application of paleoseismological techniques to the study of Late Pleistocene-Holocene deep-seated gravitational movements at the Mortirolo Pass (central Alps, Italy)

2001 ◽  
Vol 80 (3-4) ◽  
pp. 209-227 ◽  
Author(s):  
M. Onida ◽  
F. Galadini ◽  
F. Forcella
Keyword(s):  
Late Pleistocene ◽  
Large Scale ◽  
Vertical Displacement ◽  
Central Alps ◽  
Glacial Retreat ◽  
Activation Mechanisms ◽  
Loading And Unloading ◽  
Shear Planes ◽  
Geometry And Kinematics

AbstractPaleoseismological techniques have been used to investigate gravitational deformations at the Mortirolo Pass (Valtellina region, central Alps), in order to improve the knowledge on the activation mechanisms and the evolution of deep-seated gravitational slope movements. The deformation has been responsible for mass sliding towards the Valtellina depression through the activation of several-hundred-metre-long shear planes. Minor shear planes dipping towards the mountain played the role of antithetic structures. Four trenches were excavated across scarps representing the surficial expression of shear planes affecting the bedrock and Late Pleistocene-Holocene deposits. The excavations enabled to investigate the stratigraphy of Quaternary deposits and the geometry and kinematics of the shear planes affecting them. Radiocarbon analyses on organic material contained in sediments and paleosols enabled to define a succession of displacement events which occurred during the Late Pleistocene-Holocene. Collected data indicate the persistence of the activity until recent times (last movement related to 1810-1540 cal. BP). A sudden movement has been detected along one of the main shear surfaces (dipping towards the valley) with a vertical displacement of several metres. In contrast, numerous displacements (with lower vertical offset) have been detected along the antithetic shear planes. Different hypotheses have been proposed in the past to define the origin of huge gravitational movements (glacial retreat, uplift of the Alpine chain, fault activity). However, the Late Pleistocene cycles of glacial loading and unloading on the mountain slopes seem to be the most probable factors causing deep-seated gravitational movements in the investigated region. A recent dramatic landslide in an area adjacent to the investigated one (Mt. Zandila-Valpola) testifies to the paroxistic evolution of the large scale gravitational deformations. The densely inhabited Valtellina region is affected by a large number of gravitational structures similar to those of the Mortirolo area. In consideration of the possible effects of the paroxistic activation of these structures, detailed studies on the chronology and kinematics of the deformations through the application of paleoseismological techniques should therefore be encouraged.

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