scholarly journals The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A–PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine

2015 ◽  
Vol 71 (5) ◽  
pp. 1207-1215 ◽  
Author(s):  
Marina Alexeeva ◽  
Espen Åberg ◽  
Richard A. Engh ◽  
Ulli Rothweiler
Keyword(s):  
Tyrosine Phosphorylation ◽  
Conformational Changes ◽  
Drug Targets ◽  
Neuronal Development ◽  
Neurological Diseases ◽  
Disulfide Bridge ◽  
Brain Physiology ◽  
Dual Specificity ◽  
Activation Segment ◽  
Catalytic Loop

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase associated with neuronal development and brain physiology. The DYRK kinases are very unusual with respect to the sequence of the catalytic loop, in which the otherwise highly conserved arginine of the HRD motif is replaced by a cysteine. This replacement, along with the proximity of a potential disulfide-bridge partner from the activation segment, implies a potential for redox control of DYRK family activities. Here, the crystal structure of DYRK1A bound to PKC412 is reported, showing the formation of the disulfide bridge and associated conformational changes of the activation loop. The DYRK kinases represent emerging drug targets for several neurological diseases as well as cancer. The observation of distinct activation states may impact strategies for drug targeting. In addition, the characterization of PKC412 binding offers new insights for DYRK inhibitor discovery.

scholarly journals Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

2021 ◽  
Vol 22 (11) ◽  
pp. 6047
Author(s):  
Mattias F. Lindberg ◽  
Laurent Meijer
Keyword(s):  
Tyrosine Phosphorylation ◽  
Human Disease ◽  
Intracellular Signaling ◽  
Neuronal Development ◽  
Viral Infections ◽  
Current Knowledge ◽  
Lymphoblastic Leukemia ◽  
Cell Cycle Control ◽  
Megakaryoblastic Leukemia ◽  
Dual Specificity

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

Avances moleculares en el síndrome de Down y su posible aplicación en neurología

2015 ◽  
Vol 20 (1) ◽  
pp. 65-78
Author(s):  
Manuel Ramos-Kuri ◽  
Enrique Salgado-Sánchez
Keyword(s):  
Tyrosine Phosphorylation ◽  
Dual Specificity

Se revisan los avances recientes en el síndrome de Down (SD), haciendo énfasis en su terapia molecular y potencial terapéutico en enfermedades como Alzheimer (EA) y otros trastornos de déficit cognoscitivo. El SD es la principal causa de retraso mental a nivel mundial, causado por la trisomía completa o parcial del cromosoma 21, y es bien conocida su estrecha relación con la EA, de inicio muy temprano. La sobre-expresión de genes del cromosoma 21 es la principal causa del SD, pero se han identificado algunos genes especialmente importantes. Por ejemplo, el gen DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase) participa en el déficit cognitivo tanto en SD como en la EA. Su fisiopatología es porque el exceso de DYRK1A hiper fosforila a la proteína precursora de amiliode (APP) y a la unidad asociada a tubulina (TAU) proteínas bien conocidas en la génesis de la EA. Otra aplicación potencial es que los pacientes con SD presentan menor incidencia de tumores sólidos; su mecanismo es inhibiendo angiogénesis, por inhibición del factor de crecimiento vascular endotelial (VEGF) a través de la inhibición de calcineurina, gracias a la sobre-expresión del gen DSCR-1 presente en el cromosoma 21. Aunque el SD aún no cuenta con terapia específica, se realiza terapia molecular en modelos murinos con SD, con dos péptidos intestinales vasoactivos NAP y SAL. Los ratones así tratados mostraron una clara disminución en el déficit cognoscitivo, sugiriendo un alto potencial terapéutico para el SD; así como, otros tipos de retardo mental y déficit de aprendizaje.

scholarly journals Molecular mechanisms of cell death in neurological diseases

2021 ◽  
Author(s):  
Diane Moujalled ◽  
Andreas Strasser ◽  
Jeffrey R. Liddell
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Neurological Diseases ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Response To Therapy ◽  
Signalling Cascades ◽  
The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

scholarly journals Characterization of Atypical Protein Tyrosine Kinase (PTK) Genes and Their Role in Abiotic Stress Response in Rice

Plants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 664
Author(s):  
Allimuthu Elangovan ◽  
Monika Dalal ◽  
Gopinathan Kumar Krishna ◽  
Sellathdurai Devika ◽  
Ranjeet Ranjan Kumar ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
Stress Response ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Rice Genome ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Protein Tyrosine ◽  
Dual Specificity ◽  
Submergence Stress

Tyrosine phosphorylation constitutes up to 5% of the total phophoproteome. However, only limited studies are available on protein tyrosine kinases (PTKs) that catalyze protein tyrosine phosphorylation in plants. In this study, domain analysis of the 27 annotated PTK genes in rice genome led to the identification of 18 PTKs with tyrosine kinase domain. The kinase domain of rice PTKs shared high homology with that of dual specificity kinase BRASSINOSTEROID-INSENSITIVE 1 (BRI1) of Arabidopsis. In phylogenetic analysis, rice PTKs clustered with receptor-like cytoplasmic kinases-VII (RLCKs-VII) of Arabidopsis. mRNAseq analysis using Genevestigator revealed that rice PTKs except PTK9 and PTK16 express at moderate to high level in most tissues. PTK16 expression was highly abundant in panicle at flowering stage. mRNAseq data analysis led to the identification of drought, heat, salt, and submergence stress regulated PTK genes in rice. PTK14 was upregulated under all stresses. qRT-PCR analysis also showed that all PTKs except PTK10 were significantly upregulated in root under osmotic stress. Tissue specificity and abiotic stress mediated differential regulation of PTKs suggest their potential role in development and stress response of rice. The candidate dual specificity PTKs identified in this study paves way for molecular analysis of tyrosine phosphorylation in rice.

scholarly journals dDYRK2: a novel dual-specificity tyrosine-phosphorylation-regulated kinase in Drosophila

2003 ◽  
Vol 374 (2) ◽  
pp. 381-391 ◽  
Author(s):  
Pamela A. LOCHHEAD ◽  
Gary SIBBET ◽  
Ross KINSTRIE ◽  
Tava CLEGHON ◽  
Margie RYLATT ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Protein Kinases ◽  
Mutational Analysis ◽  
Kinase Domain ◽  
Activation Loop ◽  
Embryonic Neurogenesis ◽  
Founding Family ◽  
Dual Specificity ◽  
Eukaryotic Organisms

Dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs) are an emerging family of protein kinases that have been identified in all eukaryotic organisms examined to date. DYRK family members are involved in regulating key developmental and cellular processes such as neurogenesis, cell proliferation, cytokinesis and cellular differentiation. Two distinct subgroups exist, nuclear and cytosolic. In Drosophila, the founding family member minibrain, whose human orthologue maps to the Down syndrome critical region, belongs to the nuclear subclass and affects post-embryonic neurogenesis. In the present paper, we report the isolation of dDYRK2, a cytosolic DYRK and the putative product of the smell-impaired smi35A gene. This is the second such kinase described in Drosophila, but the first to be characterized at the molecular and biochemical level. dDYRK2 is an 81 kDa dual-specificity kinase that autophosphorylates on tyrosine and serine/threonine residues, but appears to phosphorylate exogenous substrates only on serine/threonine residues. It contains a YXY motif in the activation loop of the kinase domain in the same location as the TXY motif in mitogenactivated protein kinases. dDYRK2 is tyrosine-phosphorylated in vivo, and mutational analysis reveals that the activation loop tyrosines are phosphorylated and are essential for kinase activity. Finally, dDYRK2 is active at all stages of fly development, with elevated levels observed during embryogenesis and pupation.

scholarly journals GPR68 Contributes to Persistent Acidosis-Induced Activation of AGC Kinases and Tyrosine Phosphorylation in Organotypic Hippocampal Slices

2021 ◽  
Vol 15 ◽  
Author(s):  
Guokun Zhou ◽  
Xiang-ming Zha
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Neurological Diseases ◽  
Hippocampal Slices ◽  
Signaling Cascades ◽  
Dependent Manner ◽  
Cyclin Dependent Kinase ◽  
Ataxia Telangiectasia Mutated ◽  
Agc Kinases ◽  
Profiling Analysis

Persistent acidosis occurs in ischemia and multiple neurological diseases. In previous studies, acidic stimulation leads to rapid increase in intracellular calcium in neurons. However, it remains largely unclear how a prolonged acidosis alters neuronal signaling. In our previous study, we found that GPR68-mediated PKC activities are protective against acidosis-induced injury in cortical slices. Here, we first asked whether the same principle holds true in organotypic hippocampal slices. Our data showed that 1-h pH 6 induced PKC phosphorylation in a GPR68-dependent manner. Go6983, a PKC inhibitor worsened acidosis-induced neuronal injury in wild type (WT) but had no effect in GPR68−/− slices. Next, to gain greater insights into acid signaling in brain tissue, we treated organotypic hippocampal slices with pH 6 for 1-h and performed a kinome profiling analysis by Western blot. Acidosis had little effect on cyclin-dependent kinase (CDK) or casein kinase 2 activity, two members of the CMGC family, or Ataxia telangiectasia mutated (ATM)/ATM and RAD3-related (ATR) activity, but reduced the phosphorylation of MAPK/CDK substrates. In contrast, acidosis induced the activation of CaMKIIα, PKA, and Akt. Besides these serine/threonine kinases, acidosis also induced tyrosine phosphorylation. Since GPR68 is widely expressed in brain neurons, we asked whether GPR68 contributes to acidosis-induced signaling. Deleting GPR68 had no effect on acidosis-induced CaMKII phosphorylation, attenuated that of phospho-Akt and phospho-PKA substrates, while abolishing acidosis-induced tyrosine phosphorylation. These data demonstrate that prolonged acidosis activates a network of signaling cascades, mediated by AGC kinases, CaMKII, and tyrosine kinases. GPR68 is the primary mediator for acidosis-induced activation of PKC and tyrosine phosphorylation, while both GPR68-dependent and -independent mechanisms contribute to the activation of PKA and Akt.

scholarly journals Crystal structure of SARS-CoV-2 main protease in complex with a Chinese herb inhibitor shikonin

2020 ◽  
Author(s):  
Jian Li ◽  
Xuelan Zhou ◽  
Yan Zhang ◽  
Fanglin Zhong ◽  
Cheng Lin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Conformational Changes ◽  
Drug Targets ◽  
Chinese Herb ◽  
Binding Modes ◽  
High Potency ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
Catalytic Dyad ◽  
Important Drug

AbstractMain protease (Mpro, also known as 3CLpro) has a major role in the replication of coronavirus life cycle and is one of the most important drug targets for anticoronavirus agents. Here we report the crystal structure of main protease of SARS-CoV-2 bound to a previously identified Chinese herb inhibitor shikonin at 2.45 angstrom resolution. Although the structure revealed here shares similar overall structure with other published structures, there are several key differences which highlight potential features that could be exploited. The catalytic dyad His41-Cys145 undergoes dramatic conformational changes, and the structure reveals an unusual arrangement of oxyanion loop stabilized by the substrate. Binding to shikonin and binding of covalent inhibitors show different binding modes, suggesting a diversity in inhibitor binding. As we learn more about different binding modes and their structure-function relationships, it is probable that we can design more effective and specific drugs with high potency that can serve as effect SARS-CoV-2 anti-viral agents.

scholarly journals Role of Enzymes in Causing Neurological Disorders

2021 ◽  
Vol 12 (1) ◽  
pp. 466-476
Author(s):  
Vysakh Visweswaran ◽  
Roshni PR
Keyword(s):  
Neurological Disorders ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Treatment Options ◽  
Direct Result ◽  
Permanent Disability ◽  
Genetic Abnormalities ◽  
Underlying Pathology

Diseases of the nervous system are always associated with poor prognosis and limited treatment options. The fragile nature of the neurons and their inability to replicate means that neurological disorders are associated with a permanent disability. Pharmacotherapy of neurological diseases requires understanding the molecular mechanisms involved in the disease pathology. In most of the cases a faulty cellular biochemical pathway is involved, resulting from a defective enzyme. This article focusses on role of enzymes in various neurological disorders. To review pertinent literature and summarise the role of enzymes in the underlying pathology of various neurological disorders. A comprehensive literature search was conducted using PubMed, SCOPUS, J-GATE and Google Scholar and relevant papers were collected using the keywords enzymes, Alzheimer's disease, redox, thiamine, depression, neurotransmitters, epileptogenesis. The literature review highlighted the role of enzymes in major neurological disorders and their potential to be used as drug targets and biomarkers. Identifying defective enzymes gives us new molecular targets to focus on for developing more effective pharmacotherapeutic options. They can be also considered as potential biomarkers. An abnormal enzyme is most often a direct result of an underlying genetic abnormality. Identifying and screening for these genetic abnormalities can be used in early identification and prevention of disease in individuals who have a genetic predisposition. The modern advances in genetic engineering shows a lot of promise in correcting these abnormalities and development of revolutionary cures although ethical concerns remain. 

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