Java bioinformatics analysis web services for multiple sequence alignment—JABAWS:MSA

Troshin, Peter V; Procter, James B.; Barton, Geoffrey J.

doi:10.1093/bioinformatics/btr304

Cited by 108 publications

(86 citation statements)

References 10 publications

(13 reference statements)

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“…Human protein kinase domain boundaries [3,38] or the complete sequences of 17 TRB2 eukaryotic orthologues, were obtained from the UniProt database and alignments and secondary structure predictions were performed using the JalView bioinformatics suite [39]. TRB-related pseudokinase domain cancer mutations that occurred at the same site independently on more than one occasion were retrieved for TRB1, TRB2, TRB3 and SgK495 from v.71 of COSMIC (catalogue of somatic mutations in cancer) [40] and mapped to protein kinase A (PKA) using the protein kinase ontology [41,42].…”

Section: Methodsmentioning

confidence: 99%

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Bailey

Byrne

Oruganty

et al. 2015

Biochemical Journal

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The human Tribbles (TRB)-related pseudokinases are CAMK (calcium/calmodulin-dependent protein kinase)-related family members that have evolved a series of highly unusual motifs in the ‘pseudocatalytic’ domain. In canonical kinases, conserved amino acids bind to divalent metal ions and align ATP prior to efficient phosphoryl-transfer to substrates. However, in pseudokinases, atypical residues give rise to diverse and often unstudied biochemical and structural features that are thought to be central to cellular functions. TRB proteins play a crucial role in multiple signalling networks and overexpression confers cancer phenotypes on human cells, marking TRB pseudokinases out as a novel class of drug target. In the present paper, we report that the human pseudokinase TRB2 retains the ability to both bind and hydrolyse ATP weakly in vitro. Kinase activity is metal-independent and involves a catalytic lysine residue, which is conserved in TRB proteins throughout evolution alongside several unique amino acids in the active site. A similar low level of autophosphorylation is also preserved in the closely related human TRB3. By employing chemical genetics, we establish that the nucleotide-binding site of an ‘analogue-sensitive’ (AS) TRB2 mutant can be targeted with specific bulky ligands of the pyrazolo-pyrimidine (PP) chemotype. Our analysis confirms that TRB2 retains low levels of ATP binding and/or catalysis that is targetable with small molecules. Given the significant clinical successes associated with targeting of cancer-associated kinases with small molecule inhibitors, it is likely that similar approaches will be useful for further evaluating the TRB pseudokinases, with the translation of this information likely to furnish new leads for drug discovery.

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Section: Methodsmentioning

confidence: 99%

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Bailey

Byrne

Oruganty

et al. 2015

Biochemical Journal

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“…Sequence alignments and consensus sequences were derived using AlignX (a component of Vector NTI Advance 11.5.0, Invitrogen, part of Life Techologies) and JalView. 50 The Nurr1 consensus-binding motifs used in the analysis were AAAGGTCA 22 CCAAGGTCA 51 and AAGGTCAC (Jaspar: http://jaspar.genereg.net/, 52 ). The computational programs utilized were ClOVER and ORCA, which analyze human, mouse, or rat promoter sequence based on Nurr1-binding motifs (CLOVER), and these motifs along with both human and mouse promoter sequences for homology comparison (ORCA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription

Meir

Durlacher

Zheng

et al. 2014

Kidney International

131

121

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Parathyroid hormone (PTH) increases FGF23 mRNA and protein levels in vivo and in vitro. Here we tested whether the increased FGF23 expression by PTH is mediated by the orphan nuclear receptor Nurr1. PTH increased Nurr1 mRNA levels prior to elevation of FGF23 mRNA levels in UMR-106 rat osteoblast-like cells. Activation of PKA increased both FGF23 and Nurr1 mRNA levels. Modification of Nurr1 expression showed that Nurr1 is essential for the PTH-mediated increase in FGF23 and luciferase reporter gene experiments identified a functional promoter region containing several potential Nurr1 binding sites. Chromatin immunoprecipitation assays confirmed the binding of Nurr1 to these regions in the FGF23 promoter. In vivo, Nurr1 mRNA and protein levels were increased in calvaria from rats with experimental CKD together with high PTH and FGF23 expression. Calcimimetics decrease PTH and FGF23 levels in CKD patients. Importantly, in rats with experimental CKD, the calcimimetic R568 decreased PTH expression, calvaria Nurr1 mRNA and protein levels, and FGF23 mRNA. Immunohistochemistry for Nurr1 showed an increase in the number of Nurr1 expressing osteocytes in the femurs of rats with CKD and this was decreased by R568. Thus, the effect of PTH to increase FGF23 transcription is mediated by Nurr1 in vitro and in vivo. In CKD, calcimimetics decrease PTH, which in turn decreases Nurr1 and consequently FGF23.

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“…visualized with Jalview software (http://www.jalview.org/) [11]. Exome Variant Server (evs.gs.washington.edu/) [12] was used to check if the variant is found in the normal population.…”

Section: Region Amplifiedmentioning

confidence: 99%

A novel mutation in GJB1 (c.212T>G) in a Chinese family with X-linked Charcot–Marie–Tooth disease

Xiao

Tan

Zhang

et al. 2015

Journal of Clinical Neuroscience

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Java bioinformatics analysis web services for multiple sequence alignment—JABAWS:MSA

Cited by 108 publications

References 10 publications

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription

A novel mutation in GJB1 (c.212T>G) in a Chinese family with X-linked Charcot–Marie–Tooth disease

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