Vanderstraete M et al. (2013), The venus kinase receptor (VKR) family: structu...

ECB-ART-50095

BMC Genomics 2013 May 30;14:361. doi: 10.1186/1471-2164-14-361.

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The venus kinase receptor (VKR) family: structure and evolution.

Vanderstraete M , Gouignard N , Ahier A , Morel M , Vicogne J , Dissous C .

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BACKGROUND: Receptor tyrosine kinases (RTK) form a family of transmembrane proteins widely conserved in Metazoa, with key functions in cell-to-cell communication and control of multiple cellular processes. A new family of RTK named Venus Kinase Receptor (VKR) has been described in invertebrates. The VKR receptor possesses a Venus Fly Trap (VFT) extracellular module, a bilobate structure that binds small ligands to induce receptor kinase activity. VKR was shown to be highly expressed in the larval stages and gonads of several invertebrates, suggesting that it could have functions in development and/or reproduction. RESULTS: Analysis of recent genomic data has allowed us to extend the presence of VKR to five bilaterian phyla (Platyhelminthes, Arthropoda, Annelida, Mollusca, Echinodermata) as well as to the Cnidaria phylum. The presence of NveVKR in the early-branching metazoan Nematostella vectensis suggested that VKR arose before the bilaterian radiation. Phylogenetic and gene structure analyses showed that the 40 receptors identified in 36 animal species grouped monophyletically, and likely evolved from a common ancestor. Multiple alignments of tyrosine kinase (TK) and VFT domains indicated their important level of conservation in all VKRs identified up to date. We showed that VKRs had inducible activity upon binding of extracellular amino-acids and molecular modeling of the VFT domain confirmed the structure of the conserved amino-acid binding site. CONCLUSIONS: This study highlights the presence of VKR in a large number of invertebrates, including primitive metazoans like cnidarians, but also its absence from nematodes and chordates. This little-known RTK family deserves to be further explored in order to determine its evolutionary origin, its possible interest for the emergence and specialization of Metazoa, and to understand its function in invertebrate development and/or reproductive biology.

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	Figure 1. Phylogenetic construction of the VKR family. A maximum likelihood tree was generated from the 40 VKR sequences using MEGA5 under the JTT+G+I model with 100 bootstrap repetitions. Outgroups are formed by insulin receptors (IR, outgroup 1), RTK-like orphan receptors (ROR, outgroup 2) and/or EGF receptors (EGFR, outgroup 3) of the following species: A. aegypti (AaIR, AAB17094.1), A. echiniator (AeEGFR, EGI67610.1), A. gambiae (AgIR, EAA00322.3), A. mellifera (AmROR, XP_397058.4), B. impatiens (BiROR, XP_003490221.1 ), Biomphalaria glabrata (BgIR, AAF31166.1), B. mori (BmIR, NP_001037011.1), C. floridanus (CfEGFR, EFN60989.1), Crassostrea gigas (CgIR, EKC21734.1; CgROR, EKC27495.1), C. sinensis (CsROR, GAA34401.2), C. teleta (CtIR, ELT96360.1), D. melanogaster (DmIR, AAC47458.1), D. plexippus (DplIR, EHJ65074.1), D. virilis (DvEgfr, ABD64816.1), E. multilocularis (EmEGFR, CAD56486.1), H. saltator (HsIR, EFN83767.1; HsEGFR, EFN75184.1) Hydra vulgaris (HvIR, Q25197.1), Ixodes scapularis (IsIR, XP_002416224.1), Lymnaea stagnalis (LsEGFR, ABQ10634.1), Metaseiulus occidentalis (MoIR, XP_003739590.1), N. vitripennis (NvROR, XP_001601308.2; NvEGFR, XP_001602830.2), P. humanus corporis (PhcIR, XP_002430961.1), S. mansoni (SmIR1, GenBank: AAN39120.1; SmIR2, GenBank: AAV65745.2 and SER, GenBank: AAA29866.1), S. purpuratus (SpIR, XP_784376.3; SpErbB4, XP_791361.3 and ROR_Sp, XP_003729469.1) and T. castaneum (TcIR, EFA11583.1). For VKR abbreviations and accession numbers, see Table 1.
	Figure 2. Distribution of vkr genes in metazoan phyla.Vkr genes were definitely identified in Arthropoda (27 insect species), Platyhelminthes (trematode and cestodes parasites), and in Mollusca, Annelida and Echinodermata (at least in one species for each phylum). Additionally, putative VKR sequences have been detected in the genomes of many other arthropods, in the mollusc Biomphalaria glabrata, in the annelid Helobdella robusta and in the echinoderm Paracentrotus lividus. The presence of VKR has been confirmed in the cnidarian N. vectensis but not found in Hydra (H. magnipapillata and H. vulgaris) genomes. The “unclassified” TK (UTK12) [5] and the RTKS kinase [17] found respectively in the choanoflagellates Monosiga brevicollis and Salpingoeca rosetta possess an architecture similar to VKR proteins. However, no vkr gene was found in the poriferan Amphimedon queenslandica. Concerning Ctenophora, Acoela, Rotifera, Ectoprocta, Brachiopoda phyla, genomic data are currently not sufficient to assess the presence or not of vkr genes in these organisms. No vkr genes were found in Chordata (vertebrates) nor in Nematoda (worms).
	Figure 3. Schematic representation of the organisation of vkr genes. Coding sequences of genes selected in the different groups of organisms are represented. Boxes indicate respectively the positions of VFT, TM or TK domains. For each gene, arrows indicate the presence of introns at conserved positions either in several phyla (red arrows) or inside of a given phylum (black arrows). Grey arrows indicate the presence of introns at non conserved positions.
	Figure 4. Alignment of the TK sequence of VKR proteins using the CLUSTALW algorithm. Numbers I to XI correspond to the eleven subdomains conserved in protein kinase domains. Essential motifs for protein kinase activity are indicated in red. The motif G8xGxxGxV15 is required for binding of ATP and V32AxK (16×)E52 for its stabilization. The motif H147RD(L/V/I)xxRNxL156 is implicated in phosphotransfer and the triplet D194FG196 is the Mg2+ binding site. The two residues Y211 and Y212 constitute the autophosphorylation site and the motif M262(A/S)PE265 is required for stabilization of the active kinase core.
	Figure 5. Alignment of the VFT sequence of VKR proteins using the CLUSTAL W algorithm. Lobe I and Lobe II (indicated by the upper black line) and the three linkers (L1, L2, L3) constitute the structure of VFT domains. Residues highlighted in red are highly conserved in all or most VKR sequences, and residues highlighted in green correspond to the consensus amino-acid binding motif of VFT domains [24].
	Figure 6. Evolutionary conservation of residues of the VFT domain visualized on the comparative modeling of AmVKR based on mGluR5 crystal (PBP: 3lmkA). Structurally important motifs are indicated in red and residues composing the consensus amino-acid binding motif of VFT domains [24] are in green sticks (for details see Figure 5). The highly conserved residues S66, E92 and Y406, found to be important for amino-acid binding, are localized within the binding pocket, together with two conserved structural residues T108 and I109 shown in red sticks.

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