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BMC Structural Biology - Latest Articles   [more] [xml]
 2014-07-19T00:00:00Z A simple method for finding a protein¿s ligand-binding pockets
Background: This paper provides a simple and rapid method for a protein-clustering strategy. The basic idea implemented here is to use computational geometry methods to predict and characterize ligand-binding pockets of a given protein structure. In addition to geometrical characteristics of the protein structure, we consider some simple biochemical properties that help recognize the best candidates for pockets in a protein’s active site. Results: Our results are shown to produce good agreement with known empirical results. Conclusions: The method presented in this paper is a low-cost rapid computational method that could be used to classify proteins and other biomolecules, and furthermore could be useful in reducing the cost and time of drug discovery.
 2014-07-07T00:00:00Z Characterization of the SAM domain of the PKD-related protein ANKS6 and its interaction with ANKS3
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder leading to end-stage renal failure in humans. In the PKD/Mhm(cy/+) rat model of ADPKD, the point mutation R823W in the sterile alpha motif (SAM) domain of the protein ANKS6 is responsible for disease. SAM domains are known protein-protein interaction domains, capable of binding each other to form polymers and heterodimers. Despite its physiological importance, little is known about the function of ANKS6 and how the R823W point mutation leads to PKD. Recent work has revealed that ANKS6 interacts with a related protein called ANKS3. Both ANKS6 and ANKS3 have a similar domain structure, with ankyrin repeats at the N-terminus and a SAM domain at the C-terminus. Results: The SAM domain of ANKS3 is identified as a direct binding partner of the ANKS6 SAM domain. We find that ANKS3-SAM polymerizes and ANKS6-SAM can bind to one end of the polymer. We present crystal structures of both the ANKS3-SAM polymer and the ANKS3-SAM/ANKS6-SAM complex, revealing the molecular details of their association. We also learn how the R823W mutation disrupts ANKS6 function by dramatically destabilizing the SAM domain such that the interaction with ANKS3-SAM is lost. Conclusions: ANKS3 is a direct interacting partner of ANKS6. By structurally and biochemically characterizing the interaction between the ANKS3 and ANKS6 SAM domains, our work provides a basis for future investigation of how the interaction between these proteins mediates kidney function.
 2014-05-29T00:00:00Z High-resolution crystal structure of spin labelled (T21R1) azurin from Pseudomonas aeruginosa: a challenging structural benchmark for in silico spin labelling algorithms
Background: EPR-based distance measurements between spin labels in proteins have become a valuable tool in structural biology. The direct translation of the experimental distances into structural information is however often impaired by the intrinsic flexibility of the spin labelled side chains. Different algorithms exist that predict the approximate conformation of the spin label either by using pre-computed rotamer libraries of the labelled side chain (rotamer approach) or by simply determining its accessible volume (accessible volume approach). Surprisingly, comparisons with many experimental distances have shown that both approaches deliver the same distance prediction accuracy of about 3 Å. Results: Here, instead of comparing predicted and experimental distances, we test the ability of both approaches to predict the actual conformations of spin labels found in a new high-resolution crystal structure of spin labelled azurin (T21R1). Inside the crystal, the label is found in two very different environments which serve as a challenging test for the in silico approaches. Conclusions: Our results illustrate why simple and more sophisticated programs lead to the same prediciton error. Thus, a more precise treatment of the complete environment of the label and also its interactions with the environment will be needed to increase the accuracy of in silico spin labelling algorithms.
 2014-05-23T00:00:00Z Sequence analysis on the information of folding initiation segments in ferredoxin-like fold proteins
Background: While some studies have shown that the 3D protein structures are more conservative than their amino acid sequences, other experimental studies have shown that even if two proteins share the same topology, they may have different folding pathways. There are many studies investigating this issue with molecular dynamics or Go-like model simulations, however, one should be able to obtain the same information by analyzing the proteins’ amino acid sequences, if the sequences contain all the information about the 3D structures. In this study, we use information about protein sequences to predict the location of their folding segments. We focus on proteins with a ferredoxin-like fold, which has a characteristic topology. Some of these proteins have different folding segments. Results: Despite the simplicity of our methods, we are able to correctly determine the experimentally identified folding segments by predicting the location of the compact regions considered to play an important role in structural formation. We also apply our sequence analyses to some homologues of each protein and confirm that there are highly conserved folding segments despite the homologues’ sequence diversity. These homologues have similar folding segments even though the homology of two proteins’ sequences is not so high. Conclusion: Our analyses have proven useful for investigating the common or different folding features of the proteins studied.
 2014-04-24T00:00:00Z High resolution structure of cleaved Serpin 42 Da from Drosophila melanogaster
Background: The Drosophila melanogaster Serpin 42 Da gene (previously Serpin 4) encodes a serine protease inhibitor that is capable of remarkable functional diversity through the alternative splicing of four different reactive centre loop exons. Eight protein isoforms of Serpin 42 Da have been identified to date, targeting the protease inhibitor to both different proteases and cellular locations. Biochemical and genetic studies suggest that Serpin 42 Da inhibits target proteases through the classical serpin ‘suicide’ inhibition mechanism, however the crystal structure of a representative Serpin 42 Da isoform remains to be determined. Results: We report two high-resolution crystal structures of Serpin 42 Da representing the A/B isoforms in the cleaved conformation, belonging to two different space-groups and diffracting to 1.7 Å and 1.8 Å. Structural analysis reveals the archetypal serpin fold, with the major elements of secondary structure displaying significant homology to the vertebrate serpin, neuroserpin. Key residues known to have central roles in the serpin inhibitory mechanism are conserved in both the hinge and shutter regions of Serpin 42 Da. Furthermore, these structures identify important conserved interactions that appear to be of crucial importance in allowing the Serpin 42 Da fold to act as a versatile template for multiple reactive centre loops that have different sequences and protease specificities. Conclusions: In combination with previous biochemical and genetic studies, these structures confirm for the first time that the Serpin 42 Da isoforms are typical inhibitory serpin family members with the conserved serpin fold and inhibitory mechanism. Additionally, these data reveal the remarkable structural plasticity of serpins, whereby the basic fold is harnessed as a template for inhibition of a large spectrum of proteases by reactive centre loop exon ‘switching’. This is the first structure of a Drosophila serpin reported to date, and will provide a platform for future mutational studies in Drosophila to ascertain the functional role of each of the Serpin 42 Da isoforms.
 2014-04-15T00:00:00Z Designing and evaluating the MULTICOM protein local and global model quality prediction methods in the CASP10 experiment
Background: Protein model quality assessment is an essential component of generating and using protein structural models. During the Tenth Critical Assessment of Techniques for Protein Structure Prediction (CASP10), we developed and tested four automated methods (MULTICOM-REFINE, MULTICOM-CLUSTER, MULTICOM-NOVEL, and MULTICOM-CONSTRUCT) that predicted both local and global quality of protein structural models. Results: MULTICOM-REFINE was a clustering approach that used the average pairwise structural similarity between models to measure the global quality and the average Euclidean distance between a model and several top ranked models to measure the local quality. MULTICOM-CLUSTER and MULTICOM-NOVEL were two new support vector machine-based methods of predicting both the local and global quality of a single protein model. MULTICOM-CONSTRUCT was a new weighted pairwise model comparison (clustering) method that used the weighted average similarity between models in a pool to measure the global model quality. Our experiments showed that the pairwise model assessment methods worked better when a large portion of models in the pool were of good quality, whereas single-model quality assessment methods performed better on some hard targets when only a small portion of models in the pool were of reasonable quality. Conclusions: Since digging out a few good models from a large pool of low-quality models is a major challenge in protein structure prediction, single model quality assessment methods appear to be poised to make important contributions to protein structure modeling. The other interesting finding was that single-model quality assessment scores could be used to weight the models by the consensus pairwise model comparison method to improve its accuracy.
 2014-03-27T00:00:00Z Crystal structure of an engineered YopM-InlB hybrid protein
Background: The multi-domain protein InlB (internalin B) from Listeria monocytogenes is an agonist of the human receptor tyrosine kinase MET. Only the internalin domain directly interacts with MET. The internalin domain consists of seven central leucine-rich repeats (LRRs) flanked by an N-terminal helical cap domain and a C-terminal immunoglobulin-like structure. A potential function of the N-terminal cap in receptor binding could so far not be demonstrated by deleting the cap, since the cap is also implicated in nucleating folding of the LRR domain. Results: We generated an InlB variant (YopM-InlB) in which the InlB cap domain was replaced by the unrelated N-terminal capping structure of the LRR protein YopM from Yersinia enterocolitica. The crystal structure of the engineered protein shows that it folds properly. Because the first LRR is structurally closely linked to the cap domain, we exchanged LRR1 along with the cap domain. This resulted in unexpected structural changes extending to LRR2 and LRR3, which are deeply involved in MET binding. As a consequence, the binding of YopM-InlB to MET was substantially weaker than that of wild type InlB. The engineered protein was about one order of magnitude less active in colony scatter assays than wild type InlB. Conclusions: We obtained a well-behaved InlB variant with an altered N-terminal capping structure through protein design. The reduced affinity for MET precludes a straightforward interpretation of the results from cell-based assays. Still, the engineered hybrid protein induced cell scatter, suggesting that the cap is required for folding and stability of InlB but is not essential for interactions that assemble the signalling-active receptor complex. The cap swap approach described here is clearly applicable to other L. monocytogenes internalins and other LRR proteins such as YopM and may yield useful structure/function correlates within this protein family.
 2014-03-19T00:00:00Z A Sco protein among the hypothetical proteins of Bacillus lehensis G1: Its 3D macromolecular structure and association with Cytochrome C Oxidase
Background: At least a quarter of any complete genome encodes for hypothetical proteins (HPs) which are largely non-similar to other known, well-characterized proteins. Predicting and solving their structures and functions is imperative to aid understanding of any given organism as a complete biological system. The present study highlights the primary effort to classify and cluster 1202 HPs of Bacillus lehensis G1 alkaliphile to serve as a platform to mine and select specific HP(s) to be studied further in greater detail. Results: All HPs of B. lehensis G1 were grouped according to their predicted functions based on the presence of functional domains in their sequences. From the metal-binding group of HPs of the cluster, an HP termed Bleg1_2507 was discovered to contain a thioredoxin (Trx) domain and highly-conserved metal-binding ligands represented by Cys69, Cys73 and His159, similar to all prokaryotic and eukaryotic Sco proteins. The built 3D structure of Bleg1_2507 showed that it shared the βαβαββ core structure of Trx-like proteins as well as three flanking β-sheets, a 310 –helix at the N-terminus and a hairpin structure unique to Sco proteins. Docking simulations provided an interesting view of Bleg1_2507 in association with its putative cytochrome c oxidase subunit II (COXII) redox partner, Bleg1_2337, where the latter can be seen to hold its partner in an embrace, facilitated by hydrophobic and ionic interactions between the proteins. Although Bleg1_2507 shares relatively low sequence identity (47%) to BsSco, interestingly, the predicted metal-binding residues of Bleg1_2507 i.e. Cys-69, Cys-73 and His-159 were located at flexible active loops similar to other Sco proteins across biological taxa. This highlights structural conservation of Sco despite their various functions in prokaryotes and eukaryotes. Conclusions: We propose that HP Bleg1_2507 is a Sco protein which is able to interact with COXII, its redox partner and therefore, may possess metallochaperone and redox functions similar to other documented bacterial Sco proteins. It is hoped that this scientific effort will help to spur the search for other physiologically relevant proteins among the so-called “orphan” proteins of any given organism.
 2014-03-14T00:00:00Z Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11)
Background: The ubiquitous non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) plays a key role in RAS/ERK signaling downstream of most, if not all growth factors, cytokines and integrins, although its major substrates remain controversial. Mutations in PTPN11 lead to several distinct human diseases. Germ-line PTPN11 mutations cause about 50% of Noonan Syndrome (NS), which is among the most common autosomal dominant disorders. LEOPARD Syndrome (LS) is an acronym for its major syndromic manifestations: multiple Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. Frequently, LS patients have hypertrophic cardiomyopathy, and they might also have an increased risk of neuroblastoma (NS) and acute myeloid leukemia (AML). Consistent with the distinct pathogenesis of NS and LS, different types of PTPN11 mutations cause these disorders. Results: Although multiple studies have reported the biochemical and biological consequences of NS- and LS-associated PTPN11 mutations, their structural consequences have not been analyzed fully. Here we report the crystal structures of WT SHP2 and five NS/LS-associated SHP2 mutants. These findings enable direct structural comparisons of the local conformational changes caused by each mutation. Conclusions: Our structural analysis agrees with, and provides additional mechanistic insight into, the previously reported catalytic properties of these mutants. The results of our research provide new information regarding the structure-function relationship of this medically important target, and should serve as a solid foundation for structure-based drug discovery programs.
 2014-03-11T00:00:00Z Structural interrogation of phosphoproteome identified by mass spectrometry reveals allowed and disallowed regions of phosphoconformation
Background: High-throughput mass spectrometric (HT-MS) study is the method of choice for monitoring global changes in proteome. Data derived from these studies are meant for further validation and experimentation to discover novel biological insights. Here we evaluate use of relative solvent accessible surface area (rSASA) and DEPTH as indices to assess experimentally determined phosphorylation events deposited in PhosphoSitePlus. Results: Based on accessibility, we map these identifications on allowed (accessible) or disallowed (inaccessible) regions of phosphoconformation. Surprisingly a striking number of HT-MS/MS derived events (1461/5947 sites or 24.6%) are present in the disallowed region of conformation. By considering protein dynamics, autophosphorylation events and/or the sequence specificity of kinases, 13.8% of these phosphosites can be moved to the allowed region of conformation. We also demonstrate that rSASA values can be used to increase the confidence of identification of phosphorylation sites within an ambiguous MS dataset. Conclusion: While MS is a stand-alone technique for the identification of vast majority of phosphorylation events, identifications within disallowed region of conformation will benefit from techniques that independently probe for phosphorylation and protein dynamics. Our studies also imply that trapping alternate protein conformations may be a viable alternative to the design of inhibitors against mutation prone drug resistance kinases.


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BMC Bioinformatics - Latest Articles   [more] [xml]
 2014-07-29T00:00:00Z The BiSciCol Triplifier: bringing biodiversity data to the Semantic Web
Background: Recent years have brought great progress in efforts to digitize the world's biodiversity data, but integrating data from many different providers, and across research domains, remains challenging. Semantic Web technologies have been widely recognized by biodiversity scientists for their potential to help solve this problem, yet these technologies have so far seen little use for biodiversity data. Such slow uptake has been due, in part, to the relative complexity of Semantic Web technologies along with a lack of domain-specific software tools to help non-experts publish their data to the Semantic Web. Results: The BiSciCol Triplifier is new software that greatly simplifies the process of converting biodiversity data in standard, tabular formats, such as Darwin Core-Archives, into Semantic Web-ready Resource Description Framework (RDF) representations. The Triplifier uses a vocabulary based on the popular Darwin Core standard, includes both Web-based and command-line interfaces, and is fully open-source software. Conclusions: Unlike most other RDF conversion tools, the Triplifier does not require detailed familiarity with core Semantic Web technologies, and it is tailored to a widely popular biodiversity data format and vocabulary standard. As a result, the Triplifier can often fully automate the conversion of biodiversity data to RDF, thereby making the Semantic Web much more accessible to biodiversity scientists who might otherwise have relatively little knowledge of Semantic Web technologies. Easy availability of biodiversity data as RDF will allow researchers to combine data from disparate sources and analyze them with powerful linked data querying tools. However, before software like the Triplifier, and Semantic Web technologies in general, can reach their full potential for biodiversity science, the biodiversity informatics community must address several critical challenges, such as the widespread failure to use robust, globally unique identifiers for biodiversity data.


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BMC Genomics - Latest Articles   [more] [xml]
 2014-07-30T00:00:00Z Signatures of selection in sheep bred for resistance or susceptibility to gastrointestinal nematodes
Background: Gastrointestinal nematodes are one of the most serious causes of disease in domestic ruminants worldwide. There is considerable variation in resistance to gastrointestinal nematodes within and between sheep breeds, which appears to be due to underlying genetic diversity. Through selection of resistant animals, rapid genetic progress has been demonstrated in both research and commercial flocks. Recent advances in genome sequencing and genomic technologies provide new opportunities to understand the ovine host response to gastrointestinal nematodes at the molecular level, and to identify polymorphisms conferring nematode resistance. Results: Divergent lines of Romney and Perendale sheep, selectively bred for high and low faecal nematode egg count, were genotyped using the Illumina(R) Ovine SNP50 BeadChip. The resulting genome-wide SNP data were analysed for selective sweeps on loci associated with resistance or susceptibility to gastrointestinal nematode infection. Population differentiation using FST and Peddrift revealed sixteen regions, which included candidate genes involved in chitinase activity and the cytokine response. Two of the sixteen regions identified were contained within previously identified QTLs associated with nematode. Conclusions: In this study we identified fourteen novel regions associated with resistance or susceptibility to gastrointestinal nematodes. Results from this study support the hypothesis that host resistance to internal nematode parasites is likely to be controlled by a number of loci of moderate to small effects.


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BMC Biochemistry - Latest Articles   [more] [xml]
 2014-07-28T00:00:00Z Extraction, purification, kinetic and thermodynamic properties of urease from germinating Pisum Sativum L. seeds
Background: Urease, one of the highly efficient known enzymes, catalyzes the hydrolysis of urea into ammonia and carbon dioxide. The present study aimed to extract urease from pea seeds (Pisum Sativum L). The enzyme was then purified in three consequence steps: acetone precipitation, DEAE-cellulose ion-exchange chromatography, and gel filtration chromatography (Sephacryl S-200 column). Results: The purification fold was 12.85 with a yield of 40%. The molecular weight of the isolated urease was estimated by chromatography to be 269,000 Daltons. Maximum urease activity (190 U/g) was achieved at the optimum conditions of 40[degree sign]C and pH of 7.5 after 5 min of incubation. The kinetic parameters,Km and Vmax, were estimated by Lineweaver-Burk fits and found to be 500 mM and 333.3 U/g, respectively. The thermodynamic constants of activation, DeltaH, Ea, and DeltaS, were determined using Arrhenius plot and found to be 21.20 kJ/mol, 23.7 kJ/mol, and 1.18 kJ/mol/K, respectively. Conclusions: Urease was purified from germinating Pisum Sativum L. seeds. The purification fold, yield, and molecular weight were determined. The effects of pH, concentration of enzyme, temperature, concentration of substrate, and storage period on urease activity were examined. This may provide an insight on the various aspects of the property of the enzyme. The significance of extracting urease from different sources could play a good role in understanding the metabolism of urea in plants.


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Nature   [more] [xml]
 2005-01-19 Einstein is dead
Until its next revolution, much of the glory of physics will be in engineering. It is a shame that the physicists who do so much of it keep so quiet about it.

Einstein is dead

Nature 433, 179 (2005). doi:10.1038/433179a

Until its next revolution, much of the glory of physics will be in engineering. It is a shame that the physicists who do so much of it keep so quiet about it.



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Science: Current Issue   [more] [xml]
 2014-07-25 [Editorial] Ghosts from the past
2014 marks the centennial of the commencement of World War I. One connection between today and that seemingly long-ago war is how we make choices when the future seems obvious only in retrospect, in what former U.S. Secretary of State George P. Shultz refers to as a world “awash in change.” Max Hastings, in Catastrophe 1914: Europe Goes to War, summarizes his views on how the rulers of Europe allowed World War I to start, then continue with a loss of over 8.6 million soldiers: “It is more appropriate to call them deniers, who preferred to persist with supremely dangerous policies and strategies….” Author: David Titley

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