Structural Basis and Prediction of Substrate Specificity in Protein Serine͞threonine Kinases
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Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent -
Allosteric Regulation in Drug Design
Mini Review Curr Trends Biomedical Eng & Biosci Volume 4 Issue 1 - May 2017 Copyright © All rights are reserved by Ashfaq Ur Rehman DOI: 10.19080/CTBEB.2017.04.5555630 Allosteric regulation in drug design Ashfaq Ur Rehman1,2*, Shah Saud3, Nasir Ahmad4, Abdul Wadood2 and R Hamid5 1State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, China 2Department of Biochemistry, Abdul Wali Khan University Mardan, Pakistan 3Laboratory of Analytical Biochemistry and Bio separation, Shanghai Jiao Tong University, China 4Department of Chemistry, Islama College University Peshawar, Pakistan 5Department of Bioinformatics, Muhammad Ali Jinnah University Islamabad, Pakistan Submission: May 02, 2017; Published: May 23, 2017 *Corresponding author: Ashfaq Ur Rehman, State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China, Tel: ; Fax: 86-21-34204348; Email: Abstract mechanism, which are initiated through attachment of ligand or inhibitors with the protein or enzymes other than active (orthosteric) sites. ThisProtein mini review and enzymes involved play mechanism, significant types roles and in importancebiological processes of allosteric of all regulations living organisms; in drug theirdesign functions process. are regulated through allosteric Keywords: Allosteric, Activator: Drug design Introduction and ultimately cause disease. While various biological processes expressed the control at different points in life time of protein function is pivotal. As all the cell processes are under carful For the survival of all organisms the significance of protein included regulation of gene expression, translation into protein control and if not properly controls this leads to the abnormality through control of activity and at last degradation of protein [1]. -
Tyrosine Kinase – Role and Significance in Cancer
Int. J. Med. Sci. 2004 1(2): 101-115 101 International Journal of Medical Sciences ISSN 1449-1907 www.medsci.org 2004 1(2):101-115 ©2004 Ivyspring International Publisher. All rights reserved Review Tyrosine kinase – Role and significance in Cancer Received: 2004.3.30 Accepted: 2004.5.15 Manash K. Paul and Anup K. Mukhopadhyay Published:2004.6.01 Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S Nagar, Mohali, Punjab, India-160062 Abstract Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Constitutive oncogenic activation in cancer cells can be blocked by selective tyrosine kinase inhibitors and thus considered as a promising approach for innovative genome based therapeutics. The modes of oncogenic activation and the different approaches for tyrosine kinase inhibition, like small molecule inhibitors, monoclonal antibodies, heat shock proteins, immunoconjugates, antisense and peptide drugs are reviewed in light of the important molecules. As angiogenesis is a major event in cancer growth and proliferation, tyrosine kinase inhibitors as a target for anti-angiogenesis can be aptly applied as a new mode of cancer therapy. The review concludes with a discussion on the application of modern techniques and knowledge of the kinome as means to gear up the tyrosine kinase drug discovery process. -
DNA Breakpoint Assay Reveals a Majority of Gross Duplications Occur in Tandem Reducing VUS Classifications in Breast Cancer Predisposition Genes
© American College of Medical Genetics and Genomics ARTICLE Corrected: Correction DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes Marcy E. Richardson, PhD1, Hansook Chong, PhD1, Wenbo Mu, MS1, Blair R. Conner, MS1, Vickie Hsuan, MS1, Sara Willett, MS1, Stephanie Lam, MS1, Pei Tsai, CGMBS, MB (ASCP)1, Tina Pesaran, MS, CGC1, Adam C. Chamberlin, PhD1, Min-Sun Park, PhD1, Phillip Gray, PhD1, Rachid Karam, MD, PhD1 and Aaron Elliott, PhD1 Purpose: Gross duplications are ambiguous in terms of clinical cohort, while the remainder have unknown tandem status. Among interpretation due to the limitations of the detection methods that the tandem gross duplications that were eligible for reclassification, cannot infer their context, namely, whether they occur in tandem or 95% of them were upgraded to pathogenic. are duplicated and inserted elsewhere in the genome. We Conclusion: DBA is a novel, high-throughput, NGS-based method investigated the proportion of gross duplications occurring in that informs the tandem status, and thereby the classification of, tandem in breast cancer predisposition genes with the intent of gross duplications. This method revealed that most gross duplica- informing their classifications. tions in the investigated genes occurred in tandem and resulted in a Methods: The DNA breakpoint assay (DBA) is a custom, paired- pathogenic classification, which helps to secure the necessary end, next-generation sequencing (NGS) method designed to treatment options for their carriers. capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2. Genetics in Medicine (2019) 21:683–693; https://doi.org/10.1038/s41436- Results: DBA allowed us to ascertain breakpoints for 44 unique 018-0092-7 gross duplications from 147 probands. -
AGC Kinases in Mtor Signaling, in Mike Hall and Fuyuhiko Tamanoi: the Enzymes, Vol
Provided for non-commercial research and educational use only. Not for reproduction, distribution or commercial use. This chapter was originally published in the book, The Enzymes, Vol .27, published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for non-commercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who know you, and providing a copy to your institution’s administrator. All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial From: ESTELA JACINTO, AGC Kinases in mTOR Signaling, In Mike Hall and Fuyuhiko Tamanoi: The Enzymes, Vol. 27, Burlington: Academic Press, 2010, pp.101-128. ISBN: 978-0-12-381539-2, © Copyright 2010 Elsevier Inc, Academic Press. Author's personal copy 7 AGC Kinases in mTOR Signaling ESTELA JACINTO Department of Physiology and Biophysics UMDNJ-Robert Wood Johnson Medical School, Piscataway New Jersey, USA I. Abstract The mammalian target of rapamycin (mTOR), a protein kinase with homology to lipid kinases, orchestrates cellular responses to growth and stress signals. Various extracellular and intracellular inputs to mTOR are known. mTOR processes these inputs as part of two mTOR protein com- plexes, mTORC1 or mTORC2. Surprisingly, despite the many cellular functions that are linked to mTOR, there are very few direct mTOR substrates identified to date. -
Integrated Computational Approaches and Tools for Allosteric Drug Discovery
International Journal of Molecular Sciences Review Integrated Computational Approaches and Tools for Allosteric Drug Discovery Olivier Sheik Amamuddy 1 , Wayde Veldman 1 , Colleen Manyumwa 1 , Afrah Khairallah 1 , Steve Agajanian 2, Odeyemi Oluyemi 2, Gennady M. Verkhivker 2,3,* and Özlem Tastan Bishop 1,* 1 Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa; [email protected] (O.S.A.); [email protected] (W.V.); [email protected] (C.M.); [email protected] (A.K.) 2 Graduate Program in Computational and Data Sciences, Keck Center for Science and Engineering, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, CA 92866, USA; [email protected] (S.A.); [email protected] (O.O.) 3 Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA * Correspondence: [email protected] (G.M.V.); [email protected] (Ö.T.B.); Tel.: +714-516-4586 (G.M.V.); +27-46-603-8072 (Ö.T.B.) Received: 25 December 2019; Accepted: 21 January 2020; Published: 28 January 2020 Abstract: Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. -
A Calcium- and Calmodulin-Dependent Kinase I␣/ Microtubule Affinity Regulating Kinase 2 Signaling Cascade Mediates Calcium-Dependent Neurite Outgrowth
The Journal of Neuroscience, April 18, 2007 • 27(16):4413–4423 • 4413 Cellular/Molecular A Calcium- and Calmodulin-Dependent Kinase I␣/ Microtubule Affinity Regulating Kinase 2 Signaling Cascade Mediates Calcium-Dependent Neurite Outgrowth Nataliya V. Uboha,1 Marc Flajolet,2 Angus C. Nairn,1,2 and Marina R. Picciotto1 1Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, and 2Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021 Calcium is a critical regulator of neuronal differentiation and neurite outgrowth during development, as well as synaptic plasticity in adulthood. Calcium- and calmodulin-dependent kinase I (CaMKI) can regulate neurite outgrowth; however, the signal transduction cascades that lead to its physiological effects have not yet been elucidated. CaMKI␣ was therefore used as bait in a yeast two-hybrid assay and microtubule affinity regulating kinase 2 (MARK2)/Par-1b was identified as an interacting partner of CaMKI in three independent screens. The interaction between CaMKI and MARK2 was confirmed in vitro and in vivo by coimmunoprecipitation. CaMKI binds MARK2 within its kinase domain, but only if it is activated by calcium and calmodulin. Expression of CaMKI and MARK2 in Neuro-2A (N2a) cells and in primary hippocampal neurons promotes neurite outgrowth, an effect dependent on the catalytic activities of these enzymes. In addition, decreasing MARK2 activity blocks the ability of the calcium ionophore ionomycin to promote neurite outgrowth. Finally, CaMKI phosphorylates MARK2 on novel sites within its kinase domain. Mutation of these phosphorylation sites decreases both MARK2 kinase activity and its ability to promote neurite outgrowth. -
Glycogen Synthase Kinase-3 Is Activated in Neuronal Cells by G 12
The Journal of Neuroscience, August 15, 2002, 22(16):6863–6875 Glycogen Synthase Kinase-3 Is Activated in Neuronal Cells by G␣ ␣ 12 and G 13 by Rho-Independent and Rho-Dependent Mechanisms C. Laura Sayas, Jesu´ s Avila, and Francisco Wandosell Centro de Biologı´a Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Cientı´ficas, Universidad Auto´ noma de Madrid, Cantoblanco, Madrid 28049, Spain ␣ ␣ ␣ ␣ Glycogen synthase kinase-3 (GSK-3) was generally considered tively active G 12 (G 12QL) and G 13 (G 13QL) in Neuro2a cells a constitutively active enzyme, only regulated by inhibition. induces upregulation of GSK-3 activity. Furthermore, overex- Here we describe that GSK-3 is activated by lysophosphatidic pression of constitutively active RhoA (RhoAV14) also activates ␣ acid (LPA) during neurite retraction in rat cerebellar granule GSK-3 However, the activation of GSK-3 by G 13 is blocked by neurons. GSK-3 activation correlates with an increase in GSK-3 coexpression with C3 transferase, whereas C3 does not block ␣ tyrosine phosphorylation. In addition, LPA induces a GSK-3- GSK-3 activation by G 12. Thus, we demonstrate that GSK-3 is ␣ ␣ mediated hyperphosphorylation of the microtubule-associated activated by both G 12 and G 13 in neuronal cells. However, ␣ protein tau. Inhibition of GSK-3 by lithium partially blocks neu- GSK-3 activation by G 13 is Rho-mediated, whereas GSK-3 ␣ rite retraction, indicating that GSK-3 activation is important but activation by G 12 is Rho-independent. The results presented not essential for the neurite retraction progress. GSK-3 activa- here imply the existence of a previously unknown mechanism of ␣ tion by LPA in cerebellar granule neurons is neither downstream GSK-3 activation by G 12/13 subunits. -
Effect of Enzyme/Substrate Ratio on the Antioxidant Properties of Hydrolysed African Yam Bean
African Journal of Biotechnology Vol. 11(50), pp. 11086-11091, 21 June, 2012 Available online at http://www.academicjournals.org/AJB DOI: 10.5897/AJB11.2271 ISSN 1684–5315 ©2012 Academic Journals Full Length Research Paper Effect of enzyme/substrate ratio on the antioxidant properties of hydrolysed African yam bean Fasasi Olufunmilayo*, Oyebode Esther and Fagbamila Oluwatoyin Department of Food Science and Technology, P. M. B. 704, Federal University of Technology, Akure, Nigeria. Accepted 8 June, 2012 The use of natural antioxidant as compared with synthetic antioxidant in food processing is a growing trend as consumers prefer natural to synthetic antioxidant mainly on emotional ground. This study investigates the antioxidant activity of hydrolysed African yam bean (Sphenostylis sternocarpa) which is regarded as one of the neglected underutilized species (NUS) of crop in Africa and Nigeria especially to improve food security and boost the economic importance of the crop. The antioxidant properties of African yam bean hydrolysates (AYH) produced at different enzyme to substrate (E/S) ratios of 1: 100 and 3: 100 (W/V) using pepsin (pH 2.0, 37°C) were studied. 2, 2-Diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging activity of the hydrolysates was significantly influenced by the E\S ratio as DPPH radical scavenging activity ranged from 56.1 to 75.8% in AYH (1: 100) and 33.3 to 58.8% in AYH (3:100) with 1000 µg/ml having the highest DPPH radical scavenging activity. AYH (1:100) and AYH (3:100) had higher reducing activities of 0.42 and 0.23, respectively at a concentration of 1000 µg/ml. -
Regulation of Energy Substrate Metabolism in Endurance Exercise
International Journal of Environmental Research and Public Health Review Regulation of Energy Substrate Metabolism in Endurance Exercise Abdullah F. Alghannam 1,* , Mazen M. Ghaith 2 and Maha H. Alhussain 3 1 Lifestyle and Health Research Center, Health Sciences Research Center, Princess Nourah bInt. Abdulrahman University, Riyadh 84428, Saudi Arabia 2 Faculty of Applied Medical Sciences, Laboratory Medicine Department, Umm Al-Qura University, Al Abdeyah, Makkah 7607, Saudi Arabia; [email protected] 3 Department of Food Science and Nutrition, College of Food and Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia; [email protected] * Correspondence: [email protected] Abstract: The human body requires energy to function. Adenosine triphosphate (ATP) is the cellular currency for energy-requiring processes including mechanical work (i.e., exercise). ATP used by the cells is ultimately derived from the catabolism of energy substrate molecules—carbohydrates, fat, and protein. In prolonged moderate to high-intensity exercise, there is a delicate interplay between carbohydrate and fat metabolism, and this bioenergetic process is tightly regulated by numerous physiological, nutritional, and environmental factors such as exercise intensity and du- ration, body mass and feeding state. Carbohydrate metabolism is of critical importance during prolonged endurance-type exercise, reflecting the physiological need to regulate glucose homeostasis, assuring optimal glycogen storage, proper muscle fuelling, and delaying the onset of fatigue. Fat metabolism represents a sustainable source of energy to meet energy demands and preserve the ‘limited’ carbohydrate stores. Coordinated neural, hormonal and circulatory events occur during prolonged endurance-type exercise, facilitating the delivery of fatty acids from adipose tissue to the Citation: Alghannam, A.F.; Ghaith, working muscle for oxidation. -
Table S1. List of Oligonucleotide Primers Used
Table S1. List of oligonucleotide primers used. Cla4 LF-5' GTAGGATCCGCTCTGTCAAGCCTCCGACC M629Arev CCTCCCTCCATGTACTCcgcGATGACCCAgAGCTCGTTG M629Afwd CAACGAGCTcTGGGTCATCgcgGAGTACATGGAGGGAGG LF-3' GTAGGCCATCTAGGCCGCAATCTCGTCAAGTAAAGTCG RF-5' GTAGGCCTGAGTGGCCCGAGATTGCAACGTGTAACC RF-3' GTAGGATCCCGTACGCTGCGATCGCTTGC Ukc1 LF-5' GCAATATTATGTCTACTTTGAGCG M398Arev CCGCCGGGCAAgAAtTCcgcGAGAAGGTACAGATACGc M398Afwd gCGTATCTGTACCTTCTCgcgGAaTTcTTGCCCGGCGG LF-3' GAGGCCATCTAGGCCATTTACGATGGCAGACAAAGG RF-5' GTGGCCTGAGTGGCCATTGGTTTGGGCGAATGGC RF-3' GCAATATTCGTACGTCAACAGCGCG Nrc2 LF-5' GCAATATTTCGAAAAGGGTCGTTCC M454Grev GCCACCCATGCAGTAcTCgccGCAGAGGTAGAGGTAATC M454Gfwd GATTACCTCTACCTCTGCggcGAgTACTGCATGGGTGGC LF-3' GAGGCCATCTAGGCCGACGAGTGAAGCTTTCGAGCG RF-5' GAGGCCTGAGTGGCCTAAGCATCTTGGCTTCTGC RF-3' GCAATATTCGGTCAACGCTTTTCAGATACC Ipl1 LF-5' GTCAATATTCTACTTTGTGAAGACGCTGC M629Arev GCTCCCCACGACCAGCgAATTCGATagcGAGGAAGACTCGGCCCTCATC M629Afwd GATGAGGGCCGAGTCTTCCTCgctATCGAATTcGCTGGTCGTGGGGAGC LF-3' TGAGGCCATCTAGGCCGGTGCCTTAGATTCCGTATAGC RF-5' CATGGCCTGAGTGGCCGATTCTTCTTCTGTCATCGAC RF-3' GACAATATTGCTGACCTTGTCTACTTGG Ire1 LF-5' GCAATATTAAAGCACAACTCAACGC D1014Arev CCGTAGCCAAGCACCTCGgCCGAtATcGTGAGCGAAG D1014Afwd CTTCGCTCACgATaTCGGcCGAGGTGCTTGGCTACGG LF-3' GAGGCCATCTAGGCCAACTGGGCAAAGGAGATGGA RF-5' GAGGCCTGAGTGGCCGTGCGCCTGTGTATCTCTTTG RF-3' GCAATATTGGCCATCTGAGGGCTGAC Kin28 LF-5' GACAATATTCATCTTTCACCCTTCCAAAG L94Arev TGATGAGTGCTTCTAGATTGGTGTCggcGAAcTCgAGCACCAGGTTG L94Afwd CAACCTGGTGCTcGAgTTCgccGACACCAATCTAGAAGCACTCATCA LF-3' TGAGGCCATCTAGGCCCACAGAGATCCGCTTTAATGC RF-5' CATGGCCTGAGTGGCCAGGGCTAGTACGACCTCG -
Tyrosine Kinases
KEVANM SHOKAT MINIREVIEW Tyrosine kinases: modular signaling enzymes with tunable specificities Cytoplasmic tyrosine kinases are composed of modular domains; one (SHl) has catalytic activity, the other two (SH2 and SH3) do not. Kinase specificity is largely determined by the binding preferences of the SH2 domain. Attaching the SHl domain to a new SH2 domain, via protein-protein association or mutation, can thus dramatically change kinase function. Chemistry & Biology August 1995, 2:509-514 Protein kinases are one of the largest protein families identified, This is a result of the overlapping substrate identified to date; over 45 new members are identified specificities of many tyrosine kinases, which makes it each year. It is estimated that up to 4 % of vertebrate pro- difficult to dissect the individual signaling pathways by teins are protein kinases [l].The protein kinases are cate- scanning for unique target motifs [2]. gorized by their specificity for serineithreonine, tyrosine, or histidine residues. Protein tyrosine kinases account for The apparent promiscuity of individual tyrosine kinases roughly half of all kinases. They occur as membrane- is a result of their unique structural organization. bound receptors or cytoplasmic proteins and are involved Enzyme specificity is typically programmed by one in a wide variety of cellular functions, including cytokine binding site, which recognizes the substrate and also con- responses, antigen-dependent immune responses, cellular tains exquisitely oriented active-site functional groups transformation by RNA viruses, oncogenesis, regulation that help to lower the energy of the transition state for of the cell cycle, and modification of cell morphology the conversion of specific substrates to products.Tyrosine (Fig.