scholarly journals Inter-subunit Crosstalk via PDZ Synergistically Governs Allosteric Activation of Proapoptotic HtrA2

2021 ◽  
Author(s):  
Aasna L. Parui ◽  
Vandana Mishra ◽  
Shubhankar Dutta ◽  
Prasenjit Bhaumik ◽  
Kakoli Bose
Keyword(s):  
Neurodegenerative Disorders ◽  
Active Site ◽  
Energy Landscape ◽  
Residual Activity ◽  
Therapeutic Strategies ◽  
Pdz Domains ◽  
Structural Element ◽  
Allosteric Activation ◽  
Structural Details

ABSTRACTMitochondrial serine protease – High temperature requirement A2 (HtrA2), is associated with various diseases including neurodegenerative disorders and cancer. Despite availability of structural details, the reports on HtrA2’s mechanistic regulation that varies with the type of activation signals still remain non-concordant. To expound the role of regulatory PDZ domains in promoting synergistic coordination between HtrA2 subunits, we generated heterotrimeric HtrA2 variants comprising different numbers of PDZs and/or active-site mutations. Sequential deletion of PDZs from the trimeric ensemble significantly affected its residual activity in a way that proffered a hypothesis advocating intermolecular allosteric crosstalk via PDZ domains in trimeric HtrA2. Furthermore, structural and computational snapshots affirmed the role of PDZs in secondary structural element formation and coordinated reorganization of the N-terminal region and regulatory loops. Therefore, apart from providing cues for devising structure-guided therapeutic strategies, this study establishes a working model of complex allosteric regulation through a multifaceted trans-mediated cooperatively-shared energy landscape.

Vitamins and Cognition: A Nutrigenomics Perspective

2020 ◽  
Vol 16 ◽  
Author(s):  
Ayyappan Anitha ◽  
Vijitha Viswambharan ◽  
Ismail Thanseem ◽  
Mary Iype ◽  
Rahna Parakkal ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Cognitive Functions ◽  
Cognitive Impairments ◽  
Cognitive Disorders ◽  
Therapeutic Strategies ◽  
Epigenetic Factors ◽  
Future Studies ◽  
Age Related ◽  
Novel Approaches

: The rise in the prevalence of neurodegenerative and neurodevelopmental cognitive disorders combined with a lack of efficient therapeutic strategies has necessitated the need to develop alternate approaches. Dietary supplements are now being considered as a complementary and alternative medicine for cognitive impairments. Considerable evidence suggests the role of vitamins in modulating the genetic and epigenetic factors implicated in neuropsychiatric, neurodevelopmental and neurodegenerative disorders. In this review, we provide an overview on the implications of nutrigenomics with reference to vitamins that are suggested to boost cognitive functions (nootropic vitamins). Several vitamins have been found to possess antioxidant and anti-inflammatory properties which make them potential candidates in preventing or delaying age-related neurodegeneration and cognitive decline. Well-designed longitudinal studies are essential to examine the association between vitamins and cognitive functions. Future studies linking nutrition with advances in neuroscience, genomics and epigenomics would provide novel approaches to the management of cognitive disorders.

scholarly journals The Structure and Functions of PRMT5 in Human Diseases

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1074
Author(s):  
Aishat Motolani ◽  
Matthew Martin ◽  
Mengyao Sun ◽  
Tao Lu
Keyword(s):  
Neurodegenerative Disorders ◽  
Functional Role ◽  
Tumor Regression ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Type Ii ◽  
Biological Functions ◽  
Arginine Methyltransferase ◽  
Structure And Functions

Since the discovery of protein arginine methyltransferase 5 (PRMT5) and the resolution of its structure, an increasing number of papers have investigated and delineated the structural and functional role of PRMT5 in diseased conditions. PRMT5 is a type II arginine methyltransferase that catalyzes symmetric dimethylation marks on histones and non-histone proteins. From gene regulation to human development, PRMT5 is involved in many vital biological functions in humans. The role of PRMT5 in various cancers is particularly well-documented, and investigations into the development of better PRMT5 inhibitors to promote tumor regression are ongoing. Notably, emerging studies have demonstrated the pathological contribution of PRMT5 in the progression of inflammatory diseases, such as diabetes, cardiovascular diseases, and neurodegenerative disorders. However, more research in this direction is needed. Herein, we critically review the position of PRMT5 in current literature, including its structure, mechanism of action, regulation, physiological and pathological relevance, and therapeutic strategies.

scholarly journals Structural and biochemical evidence of the glucose 6-phosphate-allosteric site of maize C4-phosphoenolpyruvate carboxylase: its importance in the overall enzyme kinetics

2020 ◽  
Vol 477 (11) ◽  
pp. 2095-2114
Author(s):  
Rosario A. Muñoz-Clares ◽  
Lilian González-Segura ◽  
Javier Andrés Juárez-Díaz ◽  
Carlos Mújica-Jiménez
Keyword(s):  
Active Site ◽  
Phosphoenolpyruvate Carboxylase ◽  
Site Directed Mutagenesis ◽  
Allosteric Site ◽  
Allosteric Activation ◽  
Physiological Relevance ◽  
Phosphorylated Compounds ◽  
In The Wild ◽  
Kinetics Of

Activation of phosphoenolpyruvate carboxylase (PEPC) enzymes by glucose 6-phosphate (G6P) and other phospho-sugars is of major physiological relevance. Previous kinetic, site-directed mutagenesis and crystallographic results are consistent with allosteric activation, but the existence of a G6P-allosteric site was questioned and competitive activation—in which G6P would bind to the active site eliciting the same positive homotropic effect as the substrate phosphoenolpyruvate (PEP)—was proposed. Here, we report the crystal structure of the PEPC-C4 isozyme from Zea mays with G6P well bound into the previously proposed allosteric site, unambiguously confirming its existence. To test its functionality, Asp239—which participates in a web of interactions of the protein with G6P—was changed to alanine. The D239A variant was not activated by G6P but, on the contrary, inhibited. Inhibition was also observed in the wild-type enzyme at concentrations of G6P higher than those producing activation, and probably arises from G6P binding to the active site in competition with PEP. The lower activity and cooperativity for the substrate PEP, lower activation by glycine and diminished response to malate of the D239A variant suggest that the heterotropic allosteric activation effects of free-PEP are also abolished in this variant. Together, our findings are consistent with both the existence of the G6P-allosteric site and its essentiality for the activation of PEPC enzymes by phosphorylated compounds. Furthermore, our findings suggest a central role of the G6P-allosteric site in the overall kinetics of these enzymes even in the absence of G6P or other phospho-sugars, because of its involvement in activation by free-PEP.

Autophagy Modulators and Neuroinflammation

2020 ◽  
Vol 27 (6) ◽  
pp. 955-982 ◽  
Author(s):  
Kyoung Sang Cho ◽  
Jang Ho Lee ◽  
Jeiwon Cho ◽  
Guang-Ho Cha ◽  
Gyun Jee Song
Keyword(s):  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Scientific Interest ◽  
Therapeutic Tools ◽  
Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

The Role of PGC-1α in the Pathogenesis of Neurodegenerative Disorders

2010 ◽  
Vol 11 (10) ◽  
pp. 1262-1269 ◽  
Author(s):  
Krisztina Rona-Voros ◽  
Patrick Weydt
Keyword(s):  
Neurodegenerative Disorders

Is Immune Response Relevant in Interstitial Lung Disease?

2020 ◽  
Vol 16 (1) ◽  
pp. 18-27
Author(s):  
Manzoor M. Khan
Keyword(s):  
Immune Response ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Lung Fibrosis ◽  
Lymphocytic Infiltration ◽  
Therapeutic Strategies ◽  
Mediators Of Inflammation ◽  
Acquired Immune Responses ◽  
Novel Therapeutic Strategies

Interstitial lung disease, a term for a group of disorders, causes lung fibrosis, is mostly refractory to treatments and has a high death rate. After diagnosis the survival is up to 3 years but in some cases the patients live much longer. It involves a heterogenous group of lung diseases that exhibit progressive and irreversible destruction of the lung due to the formation of scars. This results in lung malfunction, disruption of gas exchange, and eventual death because of respiratory failure. The etiology of lung fibrosis is mostly unknown with a few exceptions. The major characteristics of the disease are comprised of injury of epithelial type II cells, increased apoptosis, chronic inflammation, monocytic and lymphocytic infiltration, accumulation of myofibroblasts, and inability to repair damaged tissue properly. These events result in abnormal collagen deposition and scarring. The inflammation process is mild, and the disease is primarily fibrotic driven. Immunosuppressants do not treat the disease but the evidence is evolving that both innate and acquired immune responses a well as the cytokines contribute to at least early progression of the disease. Furthermore, mediators of inflammation including cytokines are involved throughout the process of lung fibrosis. The diverse clinical outcome of the disease is due to different pattern of inflammatory markers. Nonetheless, the development of novel therapeutic strategies requires better understanding of the role of the immune response. This review highlights the role of the immune response in interstitial lung disease and considers the therapeutic strategies based on these observations. For this review several literature data sources were used to assess the role of the immune response in interstitial lung disease and to evaluate the possible therapeutic strategies for the disease.

Role of Flavonoids in Neurodegenerative Disorders with Special Emphasis on Tangeritin

2019 ◽  
Vol 18 (8) ◽  
pp. 581-597 ◽  
Author(s):  
Ambreen Fatima ◽  
Yasir Hasan Siddique
Keyword(s):  
Medicinal Plants ◽  
Mechanism Of Action ◽  
Neurodegenerative Disorders ◽  
Treatment Strategies ◽  
Dietary Supplementation ◽  
Plant Polyphenols ◽  
Promising Candidate ◽  
Naturally Occurring ◽  
The Brain

Flavonoids are naturally occurring plant polyphenols found universally in all fruits, vegetables and medicinal plants. They have emerged as a promising candidate in the formulation of treatment strategies for various neurodegenerative disorders. The use of flavonoid rich plant extracts and food in dietary supplementation have shown favourable outcomes. The present review describes the types, properties and metabolism of flavonoids. Neuroprotective role of various flavonoids and the possible mechanism of action in the brain against the neurodegeneration have been described in detail with special emphasis on the tangeritin.

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