Fine-tuning the extent and dynamics of binding cleft opening as a potential general regulatory mechanism in parvulin-type peptidyl prolyl isomerases

Parvulins are ubiquitous peptidyl-prolyl isomerases (PPIases) required for protein folding and regulation. Among parvulin members, Arabidopsis PIN1At, human PIN1, and yeast ESS1 share a conserved cysteine residue but differ by the presence of an N-terminal WW domain, absent in PIN1At. In this study, we have explored whether the cysteine residue of Arabidopsis PIN1At is involved in catalysis and subject to oxidative modifications. From the functional complementation of yeast ess1 mutant, we concluded that the cysteine at position 69 is mandatory for PIN1At function in vivo, unless being replaced by an Asp which is found in a few parvulin members. This result correlates with a decrease of the in vitro PPIase activity of non-functional PIN1At cysteinic variants. A decrease of PIN1At activity was observed upon H2O2 treatment. The in vitro oxidation of cysteine 69, which has an acidic pKa value of 4.9, leads to the formation of covalent dimers that are reduced by thioredoxins, or to sulfinic or sulfonic acid forms at higher H2O2 excess. These investigations highlight the importance of the sole cysteine residue of PIN1At for activity. The reversible formation of an intermolecular disulfide bond might constitute a protective or regulatory mechanism under oxidizing conditions.

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ROS Induce β-Carotene Biosynthesis Caused by Changes of Photosynthesis Efficiency and Energy Metabolism in Dunaliella salina Under Stress Conditions

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2020.613768 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yimei Xi ◽

Fantao Kong ◽

Zhanyou Chi

Keyword(s):

Dunaliella Salina ◽

Regulatory Mechanism ◽

Underlying Mechanism ◽

Stress Conditions ◽

Fine Tuning ◽

High Yield ◽

Cell Factory ◽

Carotene Content ◽

Valuable Compounds ◽

Β Carotene

The unicellular alga Dunaliella salina is regarded as a promising cell factory for the commercial production of β-carotene due to its high yield of carotenoids. However, the underlying mechanism of β-carotene accumulation is still unclear. In this study, the regulatory mechanism of β-carotene accumulation in D. salina under stress conditions was investigated. Our results indicated that there is a significant positive correlation between the cellular ROS level and β-carotene content, and the maximum quantum efficiency (Fv/Fm) of PSII is negatively correlated with β-carotene content under stress conditions. The increase of ROS was found to be coupled with the inhibition of Fv/Fm of PSII in D. salina under stress conditions. Furthermore, transcriptomic analysis of the cells cultivated with H2O2 supplementation showed that the major differentially expressed genes involved in β-carotene metabolism were upregulated, whereas the genes involved in photosynthesis were downregulated. These results indicated that ROS induce β-carotene accumulation in D. salina through fine-tuning genes which were involved in photosynthesis and β-carotene biosynthesis. Our study provided a better understanding of the regulatory mechanism involved in β-carotene accumulation in D. salina, which might be useful for overaccumulation of carotenoids and other valuable compounds in other microalgae.

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γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.614690 ◽

2020 ◽

Vol 12 ◽

Author(s):

Eitan Wong ◽

Georgia R. Frost ◽

Yue-Ming Li

Keyword(s):

Environmental Changes ◽

Regulatory Mechanism ◽

Review Article ◽

Biological Pathways ◽

Fine Tuning ◽

Enzymatic Regulation ◽

Secretase Activity ◽

Numerous Type ◽

Attractive Therapeutic Target

Described as the “proteasome of the membrane” or the “scissors in the membrane,” γ-secretase has notoriously complicated biology, and even after decades of research, the full extent of its regulatory mechanism remains unclear. γ-Secretase is an intramembrane aspartyl protease complex composed of four obligatory subunits: Nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (Pen-2), and Anterior pharynx-defective-1 (Aph-1). γ-Secretase cleaves numerous type 1 transmembrane substrates, with no apparent homology, and plays major roles in broad biological pathways such as development, neurogenesis, and cancer. Notch and the amyloid precursor protein (APP) and are undoubtedly the best-studied γ-secretase substrates because of their role in cancer and Alzheimer’s disease (AD) and therefore became the focus of increasing studies as an attractive therapeutic target. The regulation of γ-secretase is intricate and involves the function of multiple cellular entities. Recently, γ-secretase modulatory proteins (GSMPs), which are non-essential subunits and yet modulate γ-secretase activity and specificity, have emerged as an important component in guiding γ-secretase. GSMPs are responsive to cellular and environmental changes and therefore, provide another layer of regulation of γ-secretase. This type of enzymatic regulation allows for a rapid and fine-tuning of γ-secretase activity when appropriate signals appear enabling a temporal level of regulation. In this review article, we discuss the latest developments on GSMPs and implications on the development of effective therapeutics for γ-secretase-associated diseases such as AD and cancer.

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ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development

The Journal of Cell Biology ◽

10.1083/jcb.201801081 ◽

2019 ◽

Vol 218 (7) ◽

pp. 2388-2402 ◽

Cited By ~ 2

Author(s):

Liliana Osório ◽

Xuewei Wu ◽

Linsheng Wang ◽

Zhixin Jiang ◽

Carlos Neideck ◽

...

Keyword(s):

Regulatory Mechanism ◽

Primitive Streak ◽

Fine Tuning ◽

Type I ◽

Nodal Signaling ◽

Biological Functions ◽

Embryo Patterning ◽

Left Right Asymmetry ◽

Negative Regulatory Mechanism ◽

Tgf Β1

Isthmin1 (ISM1) was originally identified as a fibroblast group factor expressed in Xenopus laevis embryonic brain, but its biological functions remain unclear. The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-β cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-β1, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL–ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling.

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Role of molecular chaperones in steroid receptor action

Essays in Biochemistry ◽

10.1042/bse0400041 ◽

2004 ◽

Vol 40 ◽

pp. 41-58 ◽

Cited By ~ 149

Author(s):

William B Pratt ◽

Mario D Galigniana ◽

Yoshihiro Morishima ◽

Patrick J M Murphy

Keyword(s):

Transcriptional Activation ◽

Protein Trafficking ◽

Steroid Receptors ◽

Transcriptional Regulatory ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Receptor Action ◽

Binding Cleft ◽

Hsp 90

Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.

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Fine-Tuning Futures

ASHA Leader ◽

10.1044/leader.fq.22062017.np ◽

2017 ◽

Vol 22 (6) ◽

Author(s):

Christi Miller

Keyword(s):

Fine Tuning

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Food Safety Security: A new Concept for Enhancing Food Safety Measures

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000114 ◽

2012 ◽

Vol 82 (3) ◽

pp. 216-222 ◽

Cited By ~ 4

Author(s):

Venkatesh Iyengar ◽

Ibrahim Elmadfa

Keyword(s):

Food Safety ◽

Hazard Analysis ◽

Warning System ◽

Shared Responsibility ◽

Fine Tuning ◽

Strategic Action ◽

Surveillance Network ◽

Measurement Systems ◽

Critical Control Points ◽

The Impact

The food safety security (FSS) concept is perceived as an early warning system for minimizing food safety (FS) breaches, and it functions in conjunction with existing FS measures. Essentially, the function of FS and FSS measures can be visualized in two parts: (i) the FS preventive measures as actions taken at the stem level, and (ii) the FSS interventions as actions taken at the root level, to enhance the impact of the implemented safety steps. In practice, along with FS, FSS also draws its support from (i) legislative directives and regulatory measures for enforcing verifiable, timely, and effective compliance; (ii) measurement systems in place for sustained quality assurance; and (iii) shared responsibility to ensure cohesion among all the stakeholders namely, policy makers, regulators, food producers, processors and distributors, and consumers. However, the functional framework of FSS differs from that of FS by way of: (i) retooling the vulnerable segments of the preventive features of existing FS measures; (ii) fine-tuning response systems to efficiently preempt the FS breaches; (iii) building a long-term nutrient and toxicant surveillance network based on validated measurement systems functioning in real time; (iv) focusing on crisp, clear, and correct communication that resonates among all the stakeholders; and (v) developing inter-disciplinary human resources to meet ever-increasing FS challenges. Important determinants of FSS include: (i) strengthening international dialogue for refining regulatory reforms and addressing emerging risks; (ii) developing innovative and strategic action points for intervention {in addition to Hazard Analysis and Critical Control Points (HACCP) procedures]; and (iii) introducing additional science-based tools such as metrology-based measurement systems.

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