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Marc F Lensink, Sameer Velankar, Shoshana J Wodak
We present the sixth report evaluating the performance of methods for predicting the atomic resolution structures of protein complexes offered as targets to the community-wide initiative on the Critical Assessment of Predicted Interactions (CAPRI). The evaluation is based on a total of 20,670 predicted models for 8 protein-peptide complexes, a novel category of targets in CAPRI, and 12 protein-protein targets in CAPRI prediction Rounds held during the years 2013-2016. For two of the protein-protein targets, the focus was on the prediction of side-chain conformation and positions of interfacial water molecules...
November 16, 2016: Proteins
Yuqing Zheng, Qiang Cui
To probe the microscopic mechanisms that govern the titration behavior of buried ionizable groups, microsecond explicit solvent molecular dynamics simulations are carried out for several mutants of Staphylococcal nuclease using both fixed charge and polarizable force fields. While the ionization of Asp 66, Glu 66 and Lys 125 lead to enhanced structural fluctuations and partial unfolding of adjacent α-helical regions, the ionization of Lys 25 causes local unfolding of adjacent β sheets. Using the sampled conformational ensembles, good agreement with experimental pKa values is obtained with Poisson-Boltzmann calculations using a protein dielectric constant of 2-4 for V66D/E; slightly larger dielectric constants are needed for Lys mutants especially L25K, suggesting that structural responses beyond microseconds are involved in ionization of Lys 25...
November 16, 2016: Proteins
Mikaël Bédard, Loïka Maltais, Martin Montagne, Pierre Lavigne
c-Myc is a basic Helix-Loop-Helix Leucine Zipper (b-HLH-LZ) transcription factor deregulated in the majority of human cancers. As a heterodimer with Max, another b-HLH-LZ transcription factor, deregulated and persistent c-Myc accumulates at transcriptionally active promoters and enhancers and amplifies transcription. This leads to the so-called transcriptional addiction of tumor cells. Recent studies have showed that the c-Myc transcriptional activities can be reversed by its association with Miz-1, a POZ transcription factor containing 13 classical zinc fingers...
November 16, 2016: Proteins
Haoran Chen, Yuanfei Sun, Yang Shen
Predicting protein conformational changes from unbound structures or even homology models to bound structures remains a critical challenge for protein docking. Here we present a study directly addressing the challenge by reducing the dimensionality and narrowing the range of the corresponding conformational space. The study builds on cNMA - our new framework of partner- and contact-specific normal mode analysis that exploits encounter complexes and considers both intrinsic and induced flexibility. First, we established over a CAPRI (Critical Assessment of PRedicted Interactions) target set that the direction of conformational changes from unbound structures and homology models can be reproduced to a great extent by a small set of cNMA modes...
November 15, 2016: Proteins
Mihaly Mezei
The recently developed statistical measure for the type of residue-residue contact at protein complex interfaces, based on a parameter-free definition of contact, has been used to define a contact score that is correlated with the likelihood of correctness of a proposed complex structure. Comparing the proposed contact scores on the native structure and on a set of model structures the proposed measure was shown to generally favor the native structure but in itself was not able to reliably score the native structure to be the best...
November 12, 2016: Proteins
Liliana Anjos, Isabel Morgado, Marta Guerreiro, João C R Cardoso, Eduardo P Melo, Deborah M Power
Cartilage acidic protein1 (CRTAC1) is an extracellular matrix protein of chondrogenic tissue in humans and its presence in bacteria indicate it is of ancient origin. Structural modeling of piscine CRTAC1 reveals it belongs to the large family of beta-propeller proteins that in mammals have been associated with diseases, including amyloid diseases such as Alzheimer's. In order to characterize the structure/function evolution of this new member of the beta-propeller family we exploited the unique characteristics of piscine duplicate genes Crtac1a and Crtac1b and compared their structural and biochemical modifications with human recombinant CRTAC1...
November 12, 2016: Proteins
Chandran Nithin, Sunandan Mukherjee, Ranjit Prasad Bahadur
We present an updated version of the protein-RNA docking benchmark, which we first published four years back. The non-redundant protein-RNA docking benchmark version 2.0 consists of 126 test cases, a threefold increase in number compared to its previous version. The present version consists of 21 unbound-unbound cases, of which, in 12 cases, the unbound RNAs are taken from another complex. It also consists of 95 unbound-bound cases where only the protein is available in the unbound state. Besides, we introduce 10 new bound-unbound cases where only the RNA is found in the unbound state...
November 12, 2016: Proteins
Cooper A Taylor, Bill R Miller, Soleil S Shah, Carol A Parish
Mutations in the amyloid precursor protein (APP) are responsible for the formation of amyloid-β peptides. These peptides play a role in Alzheimer's and other dementia-related diseases. The cargo binding domain of the kinesin-1 light chain motor protein (KLC1) may be responsible for transporting APP either directly or via interaction with C-jun N-terminal kinase-interacting protein 1 (JIP1). However, to date there has been no direct experimental or computational assessment of such binding at the atomistic level...
November 7, 2016: Proteins
Robert B Crochet, Jeong-Do Kim, Herie Lee, Young-Sun Yim, Song-Gun Kim, David Neau, Yong-Hwan Lee
The heart-specific isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) is an important regulator of glycolytic flux in cardiac cells. Here, we present the crystal structures of two PFKFB2 orthologues, human and bovine, at resolutions of 2.0 and 1.8 Å, respectively. Citrate, a TCA cycle intermediate and well-known inhibitor of PFKFB2, co-crystallized in the 2-kinase domains of both orthologues, occupying the fructose-6-phosphate binding-site and extending into the γ-phosphate binding pocket of ATP...
November 1, 2016: Proteins
Yanis R Espinosa, J Raúl Grigera, Ernesto R Caffarena
The cold denaturation of globular proteins is a process that can be caused by increasing pressure or decreasing the temperature. Currently, the action mechanism of this process has not been clearly understood, raising an interesting debate on the matter. We have studied the process of cold denaturation using molecular dynamics simulations of the frataxin system Yfh1, which has a dynamic experimental characterization of unfolding at low and high temperatures. The frataxin model here studied allows a comparative analysis using experimental data...
November 1, 2016: Proteins
Clay A Foster, Ann H West
Two-component signaling (TCS) is the primary means by which bacteria, as well as certain plants and fungi, respond to external stimuli. Signal transduction involves stimulus-dependent autophosphorylation of a sensor histidine kinase and phosphoryl transfer to the receiver domain of a downstream response regulator. Phosphorylation acts as an allosteric switch, inducing structural and functional changes in the pathway's components. Due to their transient nature, phosphorylated receiver domains are challenging to characterize structurally...
November 1, 2016: Proteins
Elodie Laine, Alessandra Carbone
Cells are interactive living systems where proteins movements, interactions and regulation are substantially free from centralized management. How protein physico-chemical and geometrical properties determine who interact with whom remains far from fully understood. We show that characterizing how a protein behaves with many potential interactors in a complete cross-docking study leads to a sharp identification of its cellular/true/native partner(s). We define a sociability index, or S-index, reflecting whether a protein likes or not to pair with other proteins...
November 1, 2016: Proteins
Laura Díaz-Sáez, Genady Pankov, William N Hunter
Caseinolytic proteases are large oligomeric assemblies responsible for maintaining protein homeostasis in bacteria and in so doing influence a wide range of biological processes. The functional assembly involves three chaperones together with the oligomeric caseinolytic protease catalytic subunit P (ClpP). This protease represents a potential target for therapeutic intervention in pathogenic bacteria. Here, we detail an efficient protocol for production of recombinant ClpP from Francisella tularensis, and the structural characterization of three crystal forms which grow under similar conditions...
November 1, 2016: Proteins
Paula Korkuć, Dirk Walther
Post-translational modifications (PTMs) represent an important regulatory layer influencing the structure and function of proteins. With broader availability of experimental information on the occurrences of different PTM types, the investigation of a potential "crosstalk" between different PTM types and combinatorial effects have moved into the research focus. Hypothesizing that relevant interferences between different PTM types and sites may become apparent when investigating their mutual physical distances, we performed a systematic survey of pairwise homo- and heterotypic distances of seven frequent PTM types considering their sequence and spatial distances in resolved protein structures...
November 1, 2016: Proteins
Xianjin Xu, Liming Qiu, Chengfei Yan, Zhiwei Ma, Sam Z Grinter, Xiaoqin Zou
Protein-protein interactions are either through direct contacts between two binding partners or mediated by structural waters. Both direct contacts and water-mediated interactions are crucial to the formation of a protein-protein complex. During the recent CAPRI rounds, a novel parallel searching strategy for predicting water-mediated interactions is introduced into our protein-protein docking method, MDockPP. Briefly, a FFT-based docking algorithm is employed in generating putative binding modes, and an iteratively derived statistical potential-based scoring function, ITScorePP, in conjunction with biological information is used to assess and rank the binding modes...
November 1, 2016: Proteins
Jonathan Catazaro, Austin J Lowe, Ronald L Cerny, Robert Powers
Protein function elucidation often relies heavily on amino acid sequence analysis and other bioinformatics approaches. The reliance is extended to structure homology modeling for ligand docking and protein-protein interaction mapping. However, sequence analysis of RPA3313 exposes a large, unannotated class of hypothetical proteins mostly from the Rhizobiales order. In the absence of sequence and structure information, further functional elucidation of this class of proteins has been significantly hindered. A high quality NMR structure of RPA3313 reveals that the protein forms a novel split ββαβ fold with a conserved ligand binding pocket between the first β-strand and the N-terminus of the α-helix...
November 1, 2016: Proteins
A Vangone, J P G L M Rodrigues, L C Xue, G C P van Zundert, C Geng, Z Kurkcuoglu, M Nellen, S Narasimhan, E Karaca, M van Dijk, A S J Melquiond, K M Visscher, M Trellet, P L Kastritis, A M J J Bonvin
Our information-driven docking approach HADDOCK is a consistent top predictor and scorer since the start of its participation in the CAPRI community-wide experiment. This sustained performance is due, in part, to its ability to integrate experimental data and/or bioinformatics information into the modelling process, and also to the overall robustness of the scoring function used to assess and rank the predictions. In the CASP-CAPRI Round 1 scoring experiment we successfully selected acceptable/medium quality models for 18/14 of the 25 targets - a top-ranking performance among all scorers...
November 1, 2016: Proteins
Xianghan Mei, Jonathan Alvarez, Adriana Bon Ramos, Uttamkumar Samanta, Dirk Iwata-Reuyl, Manal A Swairjo
The tunneling-fold (T-fold) structural superfamily has emerged as a versatile protein scaffold of diverse catalytic activities. This is especially evident in the pathways to the 7-deazaguanosine modified nucleosides of tRNA queuosine and archaeosine. Four members of the T-fold superfamily have been confirmed in these pathways and here we report the crystal structure of a fifth enzyme; the recently discovered amidinotransferase QueF-Like (QueF-L), responsible for the final step in the biosynthesis of archaeosine in the D-loop of tRNA in a subset of Crenarchaeota...
November 1, 2016: Proteins
Ogun Adebali, Igor B Zhulin
Gene duplication and loss are major driving forces in evolution. While many important genomic resources provide information on gene presence, there is a lack of tools giving equal importance to presence and absence information as well as web platforms enabling easy visual comparison of multiple domain-based protein occurrences at once. Here, we present Aquerium, a platform for visualizing genomic presence and absence of biomolecules with a focus on protein domain architectures. The web server offers advanced domain organization querying against the database of pre-computed domains for ∼26,000 organisms and it can be utilized for identification of evolutionary events, such as fusion, disassociation, duplication, and shuffling of protein domains...
November 1, 2016: Proteins
Christina Em Schindler, Isaure Chauvot de Beauchêne, Sjoerd de Vries, Martin Zacharias
The ATTRACT coarse-grained docking approach in combination with various types of atomistic, flexible refinement methods has been applied to predict protein-protein and peptide-protein complexes in CAPRI rounds 28-36. For a large fraction of CAPRI targets (12 out of 18), at least one model of acceptable or better quality was generated, corresponding to a success rate of 67%. In particular, for several peptide-protein complexes excellent predictions were achieved. In several cases, a combination of template-based modeling and extensive molecular dynamics-based refinement yielded medium and even high quality solutions...
October 27, 2016: Proteins
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