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. 2011 May 6;12:215.
doi: 10.1186/1471-2164-12-215.

Eukaryotic Protein Kinases (ePKs) of the Helminth Parasite Schistosoma Mansoni

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Free PMC article

Eukaryotic Protein Kinases (ePKs) of the Helminth Parasite Schistosoma Mansoni

Luiza F Andrade et al. BMC Genomics. .
Free PMC article

Abstract

Background: Schistosomiasis remains an important parasitic disease and a major economic problem in many countries. The Schistosoma mansoni genome and predicted proteome sequences were recently published providing the opportunity to identify new drug candidates. Eukaryotic protein kinases (ePKs) play a central role in mediating signal transduction through complex networks and are considered druggable targets from the medical and chemical viewpoints. Our work aimed at analyzing the S. mansoni predicted proteome in order to identify and classify all ePKs of this parasite through combined computational approaches. Functional annotation was performed mainly to yield insights into the parasite signaling processes relevant to its complex lifestyle and to select some ePKs as potential drug targets.

Results: We have identified 252 ePKs, which corresponds to 1.9% of the S. mansoni predicted proteome, through sequence similarity searches using HMMs (Hidden Markov Models). Amino acid sequences corresponding to the conserved catalytic domain of ePKs were aligned by MAFFT and further used in distance-based phylogenetic analysis as implemented in PHYLIP. Our analysis also included the ePK homologs from six other eukaryotes. The results show that S. mansoni has proteins in all ePK groups. Most of them are clearly clustered with known ePKs in other eukaryotes according to the phylogenetic analysis. None of the ePKs are exclusively found in S. mansoni or belong to an expanded family in this parasite. Only 16 S. mansoni ePKs were experimentally studied, 12 proteins are predicted to be catalytically inactive and approximately 2% of the parasite ePKs remain unclassified. Some proteins were mentioned as good target for drug development since they have a predicted essential function for the parasite.

Conclusions: Our approach has improved the functional annotation of 40% of S. mansoni ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of S. mansoni in response to diverse environments during the parasite development, vector interaction, and host infection.

Figures

Figure 1
Figure 1
ePKinome in the predicted proteomes of diverse taxa. A total of 252 PKs were identified in the predicted proteome of S. mansoni. For comparison, the percentage (%) of the total predicted proteome that codes for kinases and the total number of ePKs (shown on top of each bar) is shown for four protozoan parasites: Pf - Plasmodium falciparum [107]; Tc - Trypanosoma cruzi, Tb - Trypanosoma brucei, Lm - Leishmania major [89]; two helminth parasites: Bm - Brugia malayi [108] and S. mansoni [26]; and five model organisms of KinBase Ce - Caernorhabditis elegans [51], Hm - Homo sapiens [13], Mm - Mus musculus [109], Dm - Drosophila melanogaster [110] and Sc - Saccharomyces cerevisiae [10].
Figure 2
Figure 2
Distribution of ePKs groups in S. mansoni and model organisms. S. mansoni proteins were classified according to KinBase [15] by combining sequence searches (HMMs) and phylogenetic analysis. For comparison, occurrence of the ePKs in B. malayi, C. elegans, H. sapiens, D. melanogaster, S. cerevisiae, and is shown. The ePK groups include: PTK (Protein Tyrosine Kinase), AGC (cAMP-dependent protein kinase/protein kinase G/protein kinase C extended), CaMK (Calcium/Calmodulin regulated kinases), CMGC (Cyclin-dependent Kinases and other close relatives), CK1 (Cell Kinase I), STE (MAP Kinase cascade kinases), RGC (Receptor Guanylate Cyclases), TKL (Tyrosine Kinase Like), and Other.
Figure 3
Figure 3
MAPK signaling pathway. MAPKs are expressed in all eukaryotic cells and are activated by diverse stimuli ranging from cytokines, growth factors, neurotransmitters, hormones, cellular stress, and cell adherence. The basic assembly of the MAPK pathway is a three-component module that includes three kinases that establish a sequential activation pathway comprising a MAPK kinase kinase (MKKK, MEKK, STE11, or STE13), MAPK kinase (MKK, MEK or STE7), and MAPK (green). The activated MAPK may translocate to the nucleus and bind to transcription factors (light blue). The mammalian MAPK can be subdivided into five families: ERK, p38, JNK, nml, and ERK5. Each MAPK family has distinct biological functions. Colored blocks correspond to proteins indentified in the S. mansoni predicted proteome and white blocks are mammals' proteins with no homologs in S. mansoni predicted proteome. The + signal represents protein activation and - signal protein inhibition by protein phosphatases (red colored proteins). S. mansoni has all representatives of ERK, p38, and JNK pathways including proteins of STE (MEK1/2, MKK), AGC (PKC and PKA), CaMK (MAPKAPK), TK (EGFR, FGFR), and TKL (Raf and TGFbeta-RI) groups.
Figure 4
Figure 4
Phylogenetic analysis of the CK1 group. Amino acid sequences of the catalytic domain of the CK1 proteins of S. mansoni (blue labels), C. elegans, D. melanogaster, S. cerevisiae, H. sapiens, and B. malayi were used to construct a distance-based phylogenetic tree using PHYLIP programs. Bootstrap values (1000 replicates) equal or higher than 80% are indicated (●) as cutoff values to support the family/subfamily classification. Functional classification is indicated individually in the protein labels. Protein families are highlighted by the vertical bars and include: VRK (Vaccinia Related Kinase), CK1 (Casein Kinase 1), TTBK (Tau Tubulin Kinase), Worm 8 (a specific family of Caenorhabditis), TTBKL (TTBK-Like kinase), and worm 6, two specific families of C. elegans and B. malayi.
Figure 5
Figure 5
Phylogenetic analysis of the paralogous ePKs groups of S. Mansoni. The catalytic domain of S. mansoni ePKs was used to construct a distance-based phylogenetic tree using PHYLIP programs. Some ePK were excluded from the tree after filtered the alighments to keep proteins with 30% to 98% pairwise sequence identity. The major ePK groups are color coded and include: CaMK (dark blue), CMGC (orange), TK (red), AGC (green), STE (pink), TKL (light blue), CK1 (yellow), and RGC (light pink). Functional classification is indicated individually in the protein. Proteins with experimental evidence (formula image) and those predicted to be inactive (⊗) due one or more substitutions in important residues in the catalytic domain are indicated. Bootstrap values (100 replicates) equal or higher than 80% are indicated (●).
Figure 6
Figure 6
S. mansoni ePKs domain architectures. Representative domain organizations of some S. mansoni ePKs belonging to the AGC, CaMK, CK1, CMGC, and STE groups are shown. Each protein ID and classification is shown below each image. Abbreviations followed are: PK_Domain (Protein kinase domain), PH_Domain (Pleckstrin Homology domain), Na_K_ATPase (Sodium/potassium ATPase beta chain), PK_C- (Protein Kinase C terminal domain), Zf-C3HC4 (zinc-finger, C3HC4 type RING finger), HR1 (Hr1 repeat), PB1 (Phox and Bem1p domain), C1_1 (Phorbol esters/diacylglycerol binding domain), C2 (Ca2+-dependent domain), CNH (citron homology domain), cNMP_binding (cyclic nucleotide-binding domain), Cofilin_ADF (Cofilin/tropomyosin-type actin-binding protein), CaMKII_AD (Calcium/calmodulin dependent protein kinase II Association), HD (HD homeobox domain), L27 (L27 domain), PDZ (PDZ domain, also known as DHR or GLGF), SH3_2 (Variant SH3 domain), Guanylate_kin (Guanylate kinase), UPF0061 (Uncharacterized ACR, YdiU/UPF0061 family), Ig (Immunoglobulin domain), fn3 (Fibronectin type III domain), V-set (Immunoglobulin V-set domain), FHA (Forkhead-associated domain), and PBD (P21-Rho-binding domain). The protein domain architectures were generated using DOG 1.0 [111] based on the Pfam domain limits [96].
Figure 7
Figure 7
Accessory Domains. Representative domain organizations of some S. mansoni ePKs belonging to the TKL, Other, TK and, RGC groups are shown. Each protein ID and classification is shown below each image. Abbreviations followed are: PK_domain (Protein kinase domain), RBD (Raf-like Ras-binding domain), C1_1 (Phorbol esters/diacylglycerol binding domain), SH3_1 (Src homology 3 domain), PBD (P21-Rho-binding domain), Ank (Ankyrin repeat), PTK_domain (Protein tyrosine kinase domain), TGF_beta_GS (Transforming growth factor beta type I GS-motif), LRR_1 (Leucine Rich Repeat), Activin_recep (Activin types I and II receptor domain) UQ_con (Ubiquitin-conjugating enzyme) TBC (TBC domain), Nucleoside_tran (Nucleoside transporter) DnaJ (DnaJ domains), SH2 (Src homology 2 domain) PH_domain (Pleckstrin Homology domain) BTK (Bruton's tyrosine kinase motif) Recep_L_domain (Receptor L domain) furin-like (Furin-like cysteine rich region) Guanylate_cyc (Receptor family ligand binding region). The protein domain architectures were generated using DOG 1.0 [111] based on the Pfam domain limits [96].

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