ConSurf: Identification of Functional Regions in Proteins
by  Surface-Mapping of Phylogenetic Information

Glaser, Fabian; Pupko, Tal; Paz, Inbal; Bell, Rachel E.; Bechor-Shental, Dalit; Martz, Eric; Ben‐Tal, Nir

doi:10.1093/bioinformatics/19.1.163

Cited by 1,101 publications

(938 citation statements)

References 14 publications

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“…The threedimensional model of human CD39 was built upon the crystal structure of CD39 from Rattus norvegicus (PDB ID 3ZX3) using SWISS-MODEL [26,27]. The mapping of conserved protein sequences were obtained via the ConSurf Server [28]. The final model was examined with PyMOL (pymol.org).…”

Section: Protein Modelingmentioning

confidence: 99%

Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma

Jiang

Wu²,

Csizmadia³

et al. 2014

Purinergic Signalling

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Phosphohydrolysis of extracellular ATP and ADP is an essential step in purinergic signaling that regulates key pathophysiological processes, such as those linked to inflammation. Classically, this reaction has been known to occur in the pericellular milieu catalyzed by membrane bound cellular ecto-nucleotidases, which can be released in the form of both soluble ecto-enzymes as well as being associated with exosomes. Circulating ecto-nucleoside triphosphate diphosphohydrolase 1 (NTPDase 1/CD39) and adenylate kinase 1 (AK1) activities have been shown to be present in plasma. However, other ecto-nucleotidases have not been characterized in depth. An in vitro ADPase assay was developed to probe the ecto-enzymes responsible for the ectonucleotidase activity in human platelet-free plasma, in combination with various specific biochemical inhibitors. Identities of ecto-nucleotidases were further characterized by chromatography, immunoblotting, and flow cytometry of circulating exosomes. We noted that microparticle-bound ENTPDases and soluble AK1 constitute the highest levels of ecto-nucleotidase activity in human plasma. All four cell membrane expressed E-NTPDases are also found in circulating microparticles in human plasma, inclusive of: CD39, NTPDase 2 (CD39L1), NTPDase 3 (CD39L3), and NTPDase 8. CD39 family members and other ecto-nucleotidases are found on distinct microparticle populations. A significant proportion of the microparticle-associated ecto-nucleotidase activity is sensitive to POM6, inferring the presence of NTPDases, either −2 or/and −3. We have refined ADPase assays of human plasma from healthy volunteers and have found that CD39, NTPDases 2, 3, and 8 to be associated with circulating microparticles, whereas soluble AK1 is present in human plasma. These ecto-enzymes constitute the bulk circulating ADPase activity, suggesting a broader implication of CD39 family and other ecto-enzymes in the regulation of extracellular nucleotide metabolism.

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Section: Protein Modelingmentioning

confidence: 99%

Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma

Jiang

Wu²,

Csizmadia³

et al. 2014

Purinergic Signalling

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“…Evolutionarily conserved residue positions as determined by the CONSURF program 25. Shown are human HO 1 ( PDB ID : 1N45) with bound heme ring in black (A) and TenA thiaminase from Pyrococcus furiosus ( PDB ID : 1RTW) with bound HMP ‐P in black (B).…”

Section: Resultsmentioning

confidence: 99%

In silico analysis of heme oxygenase structural homologues identifies group‐specific conservations

2017

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Heme oxygenases (HO) catalyze the breakdown of heme, aiding the recycling of its components. Several other enzymes have homologous tertiary structures to HOs, while sharing little sequence homology. These homologues include thiaminases, the hydroxylase component of methane monooxygenases, and the R2 component of Class I ribonucleotide reductases (RNR). This study compared these structural homologues of HO, using a large number of protein sequences for each homologue. Alignment of a total of 472 sequences showed little sequence conservation, with no residues having conservation in more than 80% of aligned sequences and only five residues conserved in at least 60% of the sequences. Fourteen additional positions, most of which were critical for hydrophobic packing, displayed amino acid similarity of 60% or higher. Ten conserved sequence motifs were identified in HOs and RNRs. Phylogenetic analysis verified the existence of the four distinct groups of HO homologues, which were then analyzed by group entropy analysis to identify residues critical to the unique function of each enzyme. Other methods for determining functional residues were also performed. Several common index positions identified represent critical evolutionary changes that resulted in the unique function of each enzyme, suggesting potential targets for site‐directed mutagenesis. These positions included residues that coordinate ligands, form the active sites, and maintain enzyme structure. Enzymes Heme oxygenase (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/14/14/18.html), methane monooxygenase (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/14/13/25.html), ribonucleotide reductase (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/17/4/1.html), thiaminase II (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/5/99/2.html).

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“…Amino acid locations subjected to positive selection were drawn onto the crystal structure using Phyre (http://www.sbg.bio.ic.ac.uk/phyre2/html) and Swiss model (http://swissmodel.expasy.org) online programs (Kelley & Sternberg, 2009). The level of evolutionary conservation amino acid/nucleic acid positions in protein was predicted using the bioinformatics tool, the ConSurf server (http://consurftest.tau.ac.il) based on phylogenetic relationship between sequences (Glaser et al., 2003). To further ratify codon sites under the selection pressure, aligned codon sequence of BMP15 and GDF9 was tested in the Selecton, version 2.2 (http://selecton.tau.ac.il/) that allows shifting the ω ratio between different codons within the aligned sequence and this was measured by maximum‐likelihood test through Bayesian inference method (Yang, Liao, Zhuang, & Zhang, 2012).…”

Section: Methodsmentioning

confidence: 99%

Maximum‐likelihood approaches reveal signatures of positive selection in BMP15 and GDF9 genes modulating ovarian function in mammalian female fertility

Ahmad

Liu

Jiang

et al. 2017

Ecology and Evolution

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Bone morphogenetic proteins (BMPs) and the growth factors (GDFs) play an important role in ovarian folliculogenesis and essential regulator of processes of numerous granulosa cells. BMP15 gene variations linked to various ovarian phenotypic consequences subject to the species, from infertility to improved prolificacy in sheep, primary ovarian insufficiency in women or associated with minor subfertility in mouse. To study the evolving role of BMP15 and GDF9, a phylogenetic analysis was performed. To find out the candidate gene associated with prolificacy in mammals, the nucleotide sequence of BMP15 and GDF9 genes was recognized under positive selection in various mammalian species. Maximum‐likelihood approaches used on BMP15 and GDF9 genes exhibited a robust divergence and a prompted evolution as compared to other TGFβ family members. Furthermore, among 32 mammalian species, we identified positive selection signals in the hominidae clade resulting to 132D, 147E, 163Y, 191W, and 236P codon sites of BMP15 and 162F, 188K, 206R, 240A, 244L, 246H, 248S, 251D, 253L, 254F and other codon sites of GDF9. The positively selected amino acid sites such as Alanine, Lucien, Arginine, and lysine are important for signaling. In conclusion, this study evidences that GDF9 and BMP15 genes have rapid evolution than other TGFß family members and was subjected to positive selection in the mammalian clade. Selected sites under the positive selection are of remarkable significance for the particular functioning of the protein and consequently for female fertility.

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ConSurf: Identification of Functional Regions in Proteins by Surface-Mapping of Phylogenetic Information

Abstract: A set of examples is available at http://consurf.tau.ac.il under 'GALLERY'.

Cited by 1,101 publications

References 14 publications

Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma

Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma

In silico analysis of heme oxygenase structural homologues identifies group‐specific conservations

Maximum‐likelihood approaches reveal signatures of positive selection in BMP15 and GDF9 genes modulating ovarian function in mammalian female fertility

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