Publications by authors named "Yves Henri Sanejouand"

By looking for a lack of homologs in a reference database of 27 well-annotated proteomes of primates and 52 well-annotated proteomes of other mammals, 170 putative human-specific proteins were identified. While most of them are deemed uncertain, 2 are known at the protein level and 23 at the transcript level, according to UniProt. Interestingly, 23 of these 25 proteins are found to be encoded or to have close homologs in an open reading frame of a long noncoding human RNA.

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To study unknown proteins on a large scale, a reference system has been set up for the three better studied eukaryotic kingdoms, built with 36 proteomes as taxonomically diverse as possible. Proteins from 362 other eukaryotic proteomes with no known homologue in this set were then analyzed, focusing noteworthy on singletons, that is, on such proteins with no known homologue in their own proteome. Consistently, for a given species, no more than 12% of the singletons thus found are known at the protein level, according to Uniprot.

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Xenon can produce general anesthesia. Its main protein target is the N-methyl-D-aspartate receptor, a ionotropic channel playing a pivotal role in the function of the central nervous system. The molecular mechanisms allowing this noble gas to have such a specific effect remain obscure, probably as a consequence of the lack of structural data at the atomic level of detail.

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Domain motions involved in the function of proteins can often be well described as a combination of motions along a handfull of low-frequency modes, that is, with the values of a few normal coordinates. This means that, when the functional motion of a protein is unknown, it should prove possible to predict it, since it amounts to guess a few values. However, without the help of additional experimental data, using normal coordinates for generating accurate conformers far away from the initial one is not so straightforward.

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Article Synopsis
  • Glycobiology struggles with a lack of synthetic oligosaccharides, and while enzyme-catalyzed glycosylation can help, it’s limited by the hydrolytic activity of glycoside hydrolases.
  • A new method uses quick in silico analysis to identify 6-12 single-mutant candidates that can enhance transglycosylation yields with minimal prior knowledge of the enzyme.
  • This approach is versatile and allows successful mutations in one enzyme to be applied to others, including those that are not closely related.
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When the hydration shell of a protein is filled with at least 0.6 gram of water per gram of protein, a significant anti-correlation between the vibrational free energy and the potential energy of energy-minimized conformers is observed. This means that low potential energy, well-hydrated, protein conformers tend to be more rigid than high-energy ones.

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Taking advantage of the known planarity of the N-acetyl group of N-acetylglucosamine, an analysis of the quality of carbohydrate structures found in the protein databank was performed. Few obvious defects of the local geometry of the carbonyl group were observed. However, the N-acetyl group was often found in the less favorable cis conformation (12% of the cases).

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Using the information available in the sequences of well-characterized transglycosidases found in plants, mutations were introduced in the glycoside hydrolase of the bacterium Thermus thermophilus, with the aim of turning it into an efficient transglycosidase. All mutants happen to have fair catalytic efficiencies, being at worst 25 times less efficient than the wild type. Noteworthy, W120F, one of our high transglycosylation yield (≈ 50%) mutants, is only two times less efficient than the wild type.

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Libraries of structural prototypes that abstract protein local structures are known as structural alphabets and have proven to be very useful in various aspects of protein structure analyses and predictions. One such library, Protein Blocks, is composed of 16 standard 5-residues long structural prototypes. This form of analyzing proteins involves drafting its structure as a string of Protein Blocks.

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The influenza pandemic of 1918-1919 killed at least 50 million people. The reasons why this pandemic was so deadly remain largely unknown [9]. However, It has been shown that the 1918 viral hemagglutinin allows to reproduce the hallmarks of the illness observed during the original pandemic [11].

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The relationship between the normal modes of a protein and its functional conformational change has been studied for decades. However, using this relationship in a predictive context remains a challenge. In this work, we demonstrate that, starting from a given protein conformer, it is possible to generate in a single step model conformers that are less than 1 Å (C -RMSD) from the conformer which is the known endpoint of the conformational change, particularly when the conformational change is collective in nature.

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Normal mode analysis is a computational technique that allows to study the dynamics of biological macromolecules. It was first applied to small protein cases, more than thirty years ago. The interest in this technique then raised when it was realized that it can provide insights about the large-scale conformational changes a protein can experience, for instance upon ligand binding.

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A large number of retaining glycosidases catalyze both hydrolysis and transglycosylation reactions. In order to use them as catalysts for oligosaccharide synthesis, the balance between these two competing reactions has to be shifted toward transglycosylation. We previously designed a semi-rational approach to convert the Thermus thermophilus β-glycosidases into transglycosidases by mutating highly conserved residues located around the -1 subsite.

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The structural annotation of proteins with no detectable homologs of known 3D structure identified using sequence-search methods is a major challenge today. We propose an original method that computes the conditional probabilities for the amino-acid sequence of a protein to fit to known protein 3D structures using a structural alphabet, known as "Protein Blocks" (PBs). PBs constitute a library of 16 local structural prototypes that approximate every part of protein backbone structures.

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A large number of retaining glycosidases catalyze both hydrolysis and transglycosylation reactions, but little is known about what determines the balance between these two activities (transglycosylation/hydrolysis ratio). We previously obtained by directed evolution the mutants F401S and N282T of Thermus thermophilus β-glycosidase (Ttβ-gly, glycoside hydrolase family 1 (GH1)), which display a higher transglycosylation/hydrolysis ratio than the wild-type enzyme. In order to find the cause of these activity modifications, and thereby set up a generic method for easily obtaining transglycosidases from glycosidases, we determined their X-ray structure.

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By taking advantage of the wealth of structural data available for family 1 glycoside hydrolases, a study of the conservation of internal water molecules found in this ubiquitous family of enzymes was undertaken. Strikingly, seven water molecules are observed in more than 90% of the known structures. To gain insight into their possible function, the water dynamics inside Thermus thermophilus β-glycosidase was probed using deuterium exchange mass spectroscopy, allowing the pinpointing of peptide L117-A125, which exchanges most of its amide hydrogens quickly in spite of the fact that it is for the most part buried in the crystal structure.

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Fifteen years ago, Monique Tirion showed that the low-frequency normal modes of a protein are not significantly altered when nonbonded interactions are replaced by Hookean springs, for all atom pairs whose distance is smaller than a given cutoff value. Since then, it has been shown that coarse-grained versions of Tirion's model are able to provide fair insights on many dynamical properties of biological macromolecules. In this chapter, theoretical tools required for studying these so-called Elastic Network Models are described, focusing on practical issues and, in particular, on possible artifacts.

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Prion diseases are fatal transmissible neurodegenerative diseases that result from structural conversion of the prion protein into a disease-associated isoform. The prion protein contains a single disulfide bond. Our analysis of all NMR structures of the prion protein (total of 440 structures over nine species) containing an explicit disulfide bond reveals that the bond exists predominantly in a stable low-energy state, but can also adopt a high-energy configuration.

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Proteins are large and complex molecular machines. In order to perform their function, most of them need energy, e.g.

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Recently, using a numerical surface cooling approach, we have shown that highly energetic discrete breathers (DBs) can form in the stiffest parts of nonlinear network models of large protein structures. In the present study, using an analytical approach, we extend our previous results to low-energy discrete breathers as well as to smaller proteins. We confirm and further scrutinize the striking site selectiveness of energy localization in the presence of spatial disorder.

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This paper describes a freely available software suite that allows the modelling of large conformational changes of high-resolution three-dimensional protein structures under the constraint of a low-resolution electron-density map. Typical applications are the interpretation of electron-microscopy data using atomic scale X-ray structural models. The software package provided should enable the interested user to perform flexible fitting on new cases without encountering major technical difficulties.

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CD4 is a coreceptor for binding of T cells to APC and the primary receptor for HIV. The disulfide bond in the second extracellular domain (D2) of CD4 is reduced on the cell surface, which leads to formation of disulfide-linked homodimers. A large conformational change must take place in D2 to allow for formation of the disulfide-linked dimer.

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It has recently been shown that disulfide bond Cys130-Cys159 in domain 2 of monomeric CD4 is involved in the formation of CD4 disulfide-bonded dimers on cell surfaces and that it can influence the permissiveness of cells to HIV infection. Because this disulfide bond is buried in the monomer, a large conformational change must take place in order to allow for such disulfide exchange. Using standard optimization techniques, whose efficiency was first checked in the well-documented CD2 case, we have shown that 3D domain swapping is a likely candidate for the conformational change, the hinge loop, or linker, being loop E-F.

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Normal mode analysis (NMA) is a powerful tool for predicting the possible movements of a given macromolecule. It has been shown recently that half of the known protein movements can be modelled by using at most two low-frequency normal modes. Applications of NMA cover wide areas of structural biology, such as the study of protein conformational changes upon ligand binding, membrane channel opening and closure, potential movements of the ribosome, and viral capsid maturation.

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Molecular replacement (MR) is the method of choice for X-ray crystallographic data phasing when structural data of suitable homologues are available. However, MR may fail even in cases of high sequence homology when conformational changes arising for example from ligand binding or different crystallogenic conditions come into play. In this work, the potential of normal-mode analysis as an extension to MR to allow recovery from such drawbacks is demonstrated.

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