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1.  When a Module is not a Domain – the Case of the REJ Module and the Redefinition of the Architecture of Polycystin-1 
The Biochemical journal  2011;435(3):651-660.
The extracellular region of a group of cell surface receptors known as the polycystic kidney disease 1 family, comprising amongst others polycystin-1, has been controversially described as containing four fibronectin type III (FNIII) domains or one REJ module in the same portion of polypeptide. Stimulated by recent atomic force microscopy work we re-examined the similarity of these four domains with a FNIII sequence profile showing the evolutionary relationship. Two of the predicted domains could be expressed in bacteria and refolded to give protein suitable for biophysical study and one of these expressed solubly. Circular dichroism spectroscopy showed that both domains contain a significant amount of β-sheet, in good agreement with theoretical predictions. Confirmation of independent folding as a domain is obtained from highly cooperative thermal and urea unfolding curves. Excellent dispersion of peaks in the high field region of one dimensional NMR spectra confirms the presence of a hydrophobic core. Analytical ultracentrifugation and analytical gel filtration agree very well with the narrow linewidths in the NMR spectra that at least one of the domains is monomeric. Based on this combined theoretical and experimental analysis we show that the extracellular portion of polycystin-1 does indeed contain β-sheet domains, very likely fibronectin type III, and that consequently the REJ module is not a single domain.
PMCID: PMC4979573  PMID: 21314639
2.  The Genome of the “Great Speciator” Provides Insights into Bird Diversification 
Genome Biology and Evolution  2015;7(9):2680-2691.
Among birds, white-eyes (genus Zosterops) have diversified so extensively that Jared Diamond and Ernst Mayr referred to them as the “great speciator.” The Zosterops lineage exhibits some of the fastest rates of species diversification among vertebrates, and its members are the most prolific passerine island colonizers. We present a high-quality genome assembly for the silvereye (Zosterops lateralis), a white-eye species consisting of several subspecies distributed across multiple islands. We investigate the genetic basis of rapid diversification in white-eyes by conducting genomic analyses at varying taxonomic levels. First, we compare the silvereye genome with those of birds from different families and searched for genomic features that may be unique to Zosterops. Second, we compare the genomes of different species of white-eyes from Lifou island (South Pacific), using whole genome resequencing and restriction site associated DNA. Third, we contrast the genomes of two subspecies of silvereye that differ in plumage color. In accordance with theory, we show that white-eyes have high rates of substitutions, gene duplication, and positive selection relative to other birds. Below genus level, we find that genomic differentiation accumulates rapidly and reveals contrasting demographic histories between sympatric species on Lifou, indicative of past interspecific interactions. Finally, we highlight genes possibly involved in color polymorphism between the subspecies of silvereye. By providing the first whole-genome sequence resources for white-eyes and by conducting analyses at different taxonomic levels, we provide genomic evidence underpinning this extraordinary bird radiation.
PMCID: PMC4607525  PMID: 26338191
genome evolution; positive selection; gene duplication; phylogenomics; demography; morphological divergence
3.  Large-Scale Modelling of the Divergent Spectrin Repeats in Nesprins: Giant Modular Proteins 
PLoS ONE  2013;8(5):e63633.
Nesprin-1 and nesprin-2 are nuclear envelope (NE) proteins characterized by a common structure of an SR (spectrin repeat) rod domain and a C-terminal transmembrane KASH [Klarsicht–ANC–Syne-homology] domain and display N-terminal actin-binding CH (calponin homology) domains. Mutations in these proteins have been described in Emery-Dreifuss muscular dystrophy and attributed to disruptions of interactions at the NE with nesprins binding partners, lamin A/C and emerin. Evolutionary analysis of the rod domains of the nesprins has shown that they are almost entirely composed of unbroken SR-like structures. We present a bioinformatical approach to accurate definition of the boundaries of each SR by comparison with canonical SR structures, allowing for a large-scale homology modelling of the 74 nesprin-1 and 56 nesprin-2 SRs. The exposed and evolutionary conserved residues identify important pbs for protein-protein interactions that can guide tailored binding experiments. Most importantly, the bioinformatics analyses and the 3D models have been central to the design of selected constructs for protein expression. 1D NMR and CD spectra have been performed of the expressed SRs, showing a folded, stable, high content α-helical structure, typical of SRs. Molecular Dynamics simulations have been performed to study the structural and elastic properties of consecutive SRs, revealing insights in the mechanical properties adopted by these modules in the cell.
PMCID: PMC3646009  PMID: 23671687
4.  OpenKnowledge for peer-to-peer experimentation in protein identification by MS/MS 
Traditional scientific workflow platforms usually run individual experiments with little evaluation and analysis of performance as required by automated experimentation in which scientists are being allowed to access numerous applicable workflows rather than being committed to a single one. Experimental protocols and data under a peer-to-peer environment could potentially be shared freely without any single point of authority to dictate how experiments should be run. In such environment it is necessary to have mechanisms by which each individual scientist (peer) can assess, locally, how he or she wants to be involved with others in experiments. This study aims to implement and demonstrate simple peer ranking under the OpenKnowledge peer-to-peer infrastructure by both simulated and real-world bioinformatics experiments involving multi-agent interactions.
A simulated experiment environment with a peer ranking capability was specified by the Lightweight Coordination Calculus (LCC) and automatically executed under the OpenKnowledge infrastructure. The peers such as MS/MS protein identification services (including web-enabled and independent programs) were made accessible as OpenKnowledge Components (OKCs) for automated execution as peers in the experiments. The performance of the peers in these automated experiments was monitored and evaluated by simple peer ranking algorithms.
Peer ranking experiments with simulated peers exhibited characteristic behaviours, e.g., power law effect (a few dominant peers dominate), similar to that observed in the traditional Web. Real-world experiments were run using an interaction model in LCC involving two different types of MS/MS protein identification peers, viz., peptide fragment fingerprinting (PFF) and de novo sequencing with another peer ranking algorithm simply based on counting the successful and failed runs. This study demonstrated a novel integration and useful evaluation of specific proteomic peers and found MASCOT to be a dominant peer as judged by peer ranking.
The simulated and real-world experiments in the present study demonstrated that the OpenKnowledge infrastructure with peer ranking capability can serve as an evaluative environment for automated experimentation.
PMCID: PMC3377912  PMID: 22192521

Results 1-4 (4)