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1787 Genome-Wide Identification and Characterization of Eukaryotic Protein Kinases Kanhu Charan Das1, Parismita Kalita1, Timir

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1787 Genome-Wide Identification and Characterization of Eukaryotic Protein Kinases Kanhu Charan Das1, Parismita Kalita1, Timir [Frontiers in Bioscience, Landmark, 25, 1787-1827, June 1, 2020] Genome-wide identification and characterization of eukaryotic protein kinases Kanhu Charan Das1, Parismita Kalita1, Timir Tripathi1 1Molecular and Structural Biophysics Laboratory, Department of Biochemistry, North-Eastern Hill University, Shillong 793022, India TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Methods 3.1. F. gigantica gene sequence retrieval 3.2. Generation of hidden markov models (HMMs) 3.3. Classification and domain analysis of FgePKs 4. Results 4.1. Identification of kinase-like proteins in F. gigantica genome 4.2. Classification and domain analysis of FgePKs 4.2.1. Ser/Thr kinase group 4.2.1.1. cAMP-dependent protein kinase (AGC) group 4.2.1.1.1. Protein kinase C (PKC) 4.2.1.1.2. Protein kinase A (PKA) 4.2.1.2. Calmodulin kinase (CaMK) group 4.2.1.3. Cyclin-dependent kinase and other close relatives (CMGC) group 4.2.1.3.1. Cyclin dependent kinases (CDK) 4.2.1.3.2. Mitogen activated protein kinases (MAPK) 4.2.1.3.3. Glycogen synthase 3 kinases (GSK3) 4.2.1.3.4. Dual-specificity Tyr regulated kinases (DYRK) 4.2.1.4. Sterile Ser/Thr kinase (STE) group 4.2.1.5. Casein kinase 1 (CK1) group 4.2.2. Tyr kinase group 4.3.3. Hybrid group 4.3.3.1. Tyr kinase-like (TKL) group 4.3.3.2. Others 5. Discussion 6. Acknowledgments 7. References 1. ABSTRACT The tropical liver fluke, Fasciola gigantica is kinases (ePKs) are regulators of cellular a food-borne parasite responsible for the phosphorylation. In the present study, we used hepatobiliary disease fascioliasis. The recent various computational and bioinformatics tools to completion of F. gigantica genome sequencing by extensively analyse the ePKs in F. gigantica our group has provided a platform for the systematic (FgePKs) genome. A total of 455 ePKs were analysis of the parasite genome. Eukaryotic protein identified that represent ~2% of the parasite genome. 1787 F. gigantica eukaryotic protein kinases Out of these, 214 ePKs are typical kinases (Ser/Thr- dephosphorylation by specialized enzymes are and Tyr-specific ePKs), and 241 were other kinases. essential to respond to certain extracellular signals Several FgePKs were found to possess unusual that help maintain homeostasis as well as other domain architectures, which suggests the diverse complex cellular adaptation in parasites. Various nature of the proteins that can be exploited for protein functions, such as cell division, cellular designing novel inhibitors. 115 kinases showed metabolism, growth, differentiation, survival, and <35% query coverage when compared to human apoptosis are regulated through phosphorylation ePKs highlighting significant divergences in their by protein kinases (PKs) that cause alterations in respective kinomes, further providing a platform for the protein structure by covalent modifications, novel structure-based drug designing. This study and hence, facilitates the formation of hydrogen provides a platform that may open new avenues into bonds among specific amino acid residues for our understanding of helminth biochemistry and drug mediating intracellular signals (15). Protein discovery. kinases catalyse the transfer of γ-phosphate from high energy molecules like ATP or GTP to its 2. INTRODUCTION polypeptide substrates, thereby, modulating their structures and functions. The action of PKs is Fascioliasis is primarily an infection of the reversed by phosphatases that remove phosphoryl livestock caused by F. hepatica and F. gigantica. It moieties from their substrates. Structurally, most is a severe food-borne neglected tropical disease PKs contain a catalytic domain responsible for (NTD) that causes massive health and economic binding and phosphorylating target proteins, and a loss in the developing countries of the tropics and regulatory domain for maintaining a catalytically subtropical areas (1-4). Fasciola spp. has a inactive state to prevent constitutive substrate worldwide distribution and it infects livestock, such phosphorylation (16). Protein kinases are either as cattle, sheep, and goats resulting in an auto phosphorylated or get phosphorylated by estimated economic loss of more than 3 billion other PKs (17). The catalytic core of the PKs USD per annum worldwide (4-6). Humans become consists of a Gly-rich ATP/GTP binding domain in accidental hosts through consumption of the N-terminus and a conserved Asp residue in the watercress or other fresh aquatic vegetation or by centre (18). Substrate recognition by PKs employs drinking water contaminated with viable parasite two types of interactions: (i) recognition of the metacercariae. Once the larvae are ingested, they consensus phosphorylation sequence by the develop into adult flukes inside the host and start active site residues and (ii) distal interactions feeding on the liver tissues. As a result, the liver between the PK and the substrate mediated by becomes dysfunctional, and the pathology is regions away from the phosphorylation site in the characterized by severe damage to the liver substrate and regions in PK located distally from tissues and bile ducts (7). According to the World its active site. Protein kinases are classified into Health Organization (WHO) estimates, at least 2.4 two superfamilies: (i) the eukaryotic or million people are infected worldwide, and 180 conventional protein kinases (ePKs), and (ii) the million are at risk of infections (8, 9). Fascioliasis atypical protein kinases (aPKs). The sequences of is principally treated with a single WHO-approved the aPKs are different than those of ePKs but show drug triclabendazole (TCBZ), but recent studies kinase activity (18). Based on the phosphate report increasing cases of TCBZ-resistant flukes in acceptor site in the substrate, ePKs are classified Europe, Australia, and in more than 70 countries into Ser/Thr kinases (STKs) and Tyr kinases (TKs). across the world (10-14). Therefore, the Kinases that specifically phosphorylate both development of new therapeutics against these Ser/Thr and Tyr are also found (19). The ePKs are platyhelminthic parasites is one of the most grouped according to their homologous catalytic important challenges for researchers. domains, which generally consist of 250-300 amino acid residues (20, 21). According to Signal transduction through the KinBase (19), ePKs have been classified into eight integration of protein phosphorylation and groups: AGC (cAMP-dependent Protein Kinase or 1788 © 1996-2020 F. gigantica eukaryotic protein kinases F. gigantica is a major step towards these goals. Alteration in the functionality of these enzymes may result in a cascade of pathological signs that might contribute to the mortality of the parasite. Thus, the present work aims at analysing the F. gigantica genome by combined computational approaches, including Hidden Markov Models (HMMs) and phylogenetic analyses to identify all the ePKs encoded in the genome; and to identify potential kinases having a special role in the signalling process of the parasite to utilize them as a novel drug target against F. gigantica. The schematic representation of the methodology is shown in Figure 1. 3. METHODS 3.1. F. gigantica gene sequence retrieval The whole genome data of F. gigantica (accession number: MKHB00000000) showed a total of 20,858 genes (25). Gene sequences were then submitted to BLAST against expressed Figure 1. Schematic representation of the methods used for search tag (EST) to ascertain the expressed prediction and classification of the F. gigantica ePKs. genes. Protein Kinase A/Protein Kinase G/Protein Kinase 3.2. Generation of hidden markov models C), CAMK (Calcium/Calmodulin regulated (HMMs) Kinases), CK1 (Cell Kinase I), CMGC (Cyclin- dependent Kinases and other close relatives), Potential ePKs of F. gigantica (FgePKs) RGC (Receptor Guanylate Cyclases), STE (Sterile were identified and characterized by combined Ser/Thr Kinases), TK (Tyr Kinase), and TKL (Tyr approaches based on sequence similarity and Kinase-Like). In addition, a ninth group called phylogenetic relationships. The gene sequences ''Other kinases'' exists, consisting of several were further translated to amino acid sequences kinases that cannot be classified into any of the using SMS server (http://www.bioinformatics.- above families (22). Many PK inhibitors have been org/sms2/translate.html) to run HMMs. developed and approved for the treatment of Alignments were generated in Mega v7 different human diseases, including infections with (www.megasoftware.net) using the clustalW parasitic helminth, like Schistosoma mansoni (the algorithm with default parameters. The HMM blood fluke) (23, 24). search was performed against the Uniprot database for identifying ePK-like proteins of F. Recent sequencing of the F. gigantica gigantica based on similarity. Also, the 20,858 F. genome (25) has provided a crucial platform for gigantica genes were directly submitted to further exploration of the biochemistry of the BLASTX that annotates the genes based on parasite. Understanding the structure and sequence similarity by converting the gene function of proteins encoded by the genome of sequences into protein sequences. The potential this platyhelminthic parasite will provide FgePKs, obtained from both HMMsearch and information for structure-based drug design and BLASTX results, were compared and used for development. Therefore, the study of the ePKs of further analysis. 1789 © 1996-2020 F. gigantica eukaryotic protein kinases 3.3. Classification and domain analysis of Trypanosoma brucei, Trypanosoma cruzi, FgePKs Leishmania
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