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Your search keyword '"Grauffel, Cédric"' showing total 154 results
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154 results on '"Grauffel, Cédric"'

2. Structural analysis of disease-related TDP-43 D169G mutation: linking enhanced stability and caspase cleavage efficiency to protein accumulation

Author

Chiang, Chien-Hao, Grauffel, Cédric, Wu, Lien-Szu, Kuo, Pan-Hsien, Doudeva, Lyudmila G, Lim, Carmay, Shen, Che-Kun James, and Yuan, Hanna S

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Genetics, Neurosciences, Brain Disorders, Neurodegenerative, ALS, Aetiology, 2.1 Biological and endogenous factors, Amino Acid Substitution, Caspases, Codon, DNA, DNA-Binding Proteins, Humans, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Dynamics Simulation, Mutation, Protein Conformation, Protein Denaturation, Protein Stability, Proteolysis, Thermodynamics
Abstract

The RNA-binding protein TDP-43 forms intracellular inclusions in amyotrophic lateral sclerosis (ALS). While TDP-43 mutations have been identified in ALS patients, how these mutations are linked to ALS remains unclear. Here we examined the biophysical properties of six ALS-linked TDP-43 mutants and found that one of the mutants, D169G, had higher thermal stability than wild-type TDP-43 and that it was cleaved by caspase 3 more efficiently, producing increased levels of the C-terminal 35 kD fragments (TDP-35) in vitro and in neuroblastoma cells. The crystal structure of the TDP-43 RRM1 domain containing the D169G mutation in complex with DNA along with molecular dynamics simulations reveal that the D169G mutation induces a local conformational change in a β turn and increases the hydrophobic interactions in the RRM1 core, thus enhancing the thermal stability of the RRM1 domain. Our results provide the first crystal structure of TDP-43 containing a disease-linked D169G mutation and a disease-related mechanism showing that D169G mutant is more susceptible to proteolytic cleavage by caspase 3 into the pathogenic C-terminal 35-kD fragments due to its increased stability in the RRM1 domain. Modulation of TDP-43 stability and caspase cleavage efficiency could present an avenue for prevention and treatment of TDP-43-linked neurodegeneration.

Published
2016

5. Α γ-tubulin complex-dependent pathway suppresses ciliogenesis by promoting cilia disassembly

Author

Shankar, Sahana, primary, Hsu, Zi-Ting, additional, Ezquerra, Artur, additional, Li, Chien-Chien, additional, Huang, Tzu-Lun, additional, Coyaud, Etienne, additional, Viais, Ricardo, additional, Grauffel, Cédric, additional, Raught, Brian, additional, Lim, Carmay, additional, Lüders, Jens, additional, Tsai, Su-Yi, additional, and Hsia, Kuo-Chiang, additional

Published
2022
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12. Factors allowing small monovalent Li+ to displace Ca2+ in proteins.

Author

Grauffel, Cédric, Weng, Wei-Hsiang, and Lim, Carmay

Abstract

Because Li+ and Ca2+ differ in both charge and size, the possibility that monovalent Li+ could dislodge the bulkier, divalent Ca2+ in Ca2+ proteins had not been considered. However, our recent density functional theory/continuum dielectric calculations predicted that Li+ could displace the native Ca2+ from the C2 domain of cytosolic PKCα/γ. This would reduce electrostatic interactions between the Li+-bound C2 domain and the membrane, consistent with experimental studies showing that Li+ can inhibit the translocation of cytoplasmic PKC to membranes. Besides the trinuclear Ca2+-site in the PKCα/γ C2 domain, it is not known whether other Ca2+-sites in human proteins may be susceptible to Li+ substitution. Furthermore, it is unclear what factors determine the outcome of the competition between divalent Ca2+ and monovalent Li+. Here we show that the net charge of residues in the first and second coordination shell is a key determinant of the selectivity for divalent Ca2+ over monovalent Li+ in proteins: neutral/anionic Ca2+-carboxylate sites are protected against Li+ attack. They are further protected by outer-shell Asp−/Glu− and the protein matrix rigidifying the Ca2+-site or limiting water entry. In contrast, buried, cationic Ca2+-sites surrounded by Arg+/Lys+, which are found in the C2 domains of PKCα/γ, as well as certain synaptotagmins, are prone to Li+ attack. [ABSTRACT FROM AUTHOR]

Published
2022
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14. Allosteric coupling between transmembrane segment 4 and the selectivity filter of TALK1 potassium channels regulates their gating by extracellular pH.

Author

Wen-Hao Tsai, Grauffel, Cédric, Ming-Yueh Huang, Postic, Sandra, Rupnik, Marjan Slak, Lim, Carmay, and Shi-Bing Yang

Subjects
*POTASSIUM channels, *CARBONYL group, *MOLECULAR dynamics
Abstract

Opening of two-pore domain K+ channels (K2Ps) is regulated by various external cues, such as pH, membrane tension, or temperature, which allosterically modulate the selectivity filter (SF) gate. However, how these cues cause conformational changes in the SF of some K2P channels remains unclear. Herein, we investigate the mechanisms by which extracellular pH affects gating in an alkaline-activated K2P channel, TALK1, using electrophysiology and molecular dynamics (MD) simulations. We show that R233, located at the N-terminal end of transmembrane segment 4, is the primary pHo sensor. This residue distally regulates the orientation of the carbonyl group at the S1 potassium-binding site through an interacting network composed of residues on transmembrane segment 4, the pore helix domain 1, and the SF. Moreover, in the presence of divalent cations, we found the acidic pH-activated R233E mutant recapitulates the network interactions of protonated R233. Intriguingly, our data further suggested stochastic coupling between R233 and the SF gate, which can be described by an allosteric gating model. We propose that this allosteric model could predict the hybrid pH sensitivity in heterodimeric channels with alkaline-activated and acidic-activated K2P subunits. [ABSTRACT FROM AUTHOR]

Published
2022
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31. KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

Author

Fournier, Marjorie, primary, Orpinell, Meritxell, additional, Grauffel, Cédric, additional, Scheer, Elisabeth, additional, Garnier, Jean-Marie, additional, Ye, Tao, additional, Chavant, Virginie, additional, Joint, Mathilde, additional, Esashi, Fumiko, additional, Dejaegere, Annick, additional, Gönczy, Pierre, additional, and Tora, László, additional

Published
2016
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33. Why Cellular Di/Triphosphates Preferably Bind Mg2+and Not Ca2+

Author

Grauffel, Cédric, Dudev, Todor, and Lim, Carmay

Abstract

Di/triphosphates perform a multitude of essential tasks, being important components of many vital organic cofactors such as adenosine/guanosine di/triphosphate (ADP/GDP, ATP/GTP), flavin adenine dinucleotide, and nicotinamide adenine dinucleotide and its phosphate derivative. They are generally bound to cations inside cells, in particular Mg2+in the case of ATP/GTP. Yet how their metal-binding modes depend on the number, charge, and solvent exposure of the polyphosphate group and how Mg2+and Ca2+dications that coexist in cellular fluids compete for di/triphosphates in biological systems remain elusive. Using density functional theory calculations combined with a polarizable continuum model, we have determined the relative free energies and stabilities of the different binding modes of di- and triphosphate groups to Mg2+and Ca2+. We show that the thermodynamic outcome of the competition between Mg2+and Ca2+for cellular di/triphosphates depends mainly on the oligomericity/charge and metal-binding mode of the phosphate ligand as well as the solvent exposure of the binding site. Increasing the charge and thus denticity of the phosphate ligand from bi- to tridentate in a buried binding pocket enhances the affinity of the host system for the stronger charge acceptor, Mg2+. The cellular di/triphosphates’s intrinsic properties and the protein matrix allowing them to bind a dication bi/tridentately, along with the higher cytosolic concentration of Mg2+compared to Ca2+, enables Mg2+to outcompete Ca2+in binding to these highly charged anions. This suggests an explanation for why nature has chosen Mg2+but not Ca2+to perform most of the essential tasks associated with biological triphosphates.

Published
2019
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35. An efficient protocol for computing the pKa of Zn-bound water.

Author

Grauffel, Cédric, Chu, Benjamin, and Lim, Carmay

Abstract

At a given pH, whether a metal-bound water molecule is deprotonated or not can be determined if the pKa of the metal-bound water molecule (denoted pKw) is known. Although protocols/tools to predict the protonation states of titratable amino acid residues and small molecules have been developed, an efficient and accurate method to predict the absolute pKw values of metal complexes is lacking. Here, we present calibrated methods for optimizing the geometries and computing the absolute pKw values of a wide range of Zn2+-complexes containing protein-like ligating groups. We tested 18 different geometry-optimization methods on 19 ultra high-resolution structures of Zn2+ complexes of varying coordination numbers and ligating atoms and 98 methods in reproducing 36 experimental pKw values of diverse Zn2+ complexes in the absence and presence of explicit water molecules. The results underscore the importance of estimating the Zn2+-bound water/hydroxide solvation properly, whereas correcting for the basis set superposition error was not found to be important. The protocol presented can be used to (i) evaluate the geometries of the different Zn2+-sites found in proteins and (ii) to dissect the individual contributions of the various factors modulating the pKw in Zn2+-sites found in proteins. Predicting absolute pKw values in various environments with efficiency and accuracy will indicate when a Zn2+-bound water molecule is deprotonated, thus providing physical insight into the mechanisms of enzyme-catalyzed reactions and the design of drug candidates that can displace a metal-bound water molecule. [ABSTRACT FROM AUTHOR]

Published
2018
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39. Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles

Author

Martin, Katherine R., primary, Kantari-Mimoun, Chahrazade, additional, Yin, Min, additional, Pederzoli-Ribeil, Magali, additional, Angelot-Delettre, Fanny, additional, Ceroi, Adam, additional, Grauffel, Cédric, additional, Benhamou, Marc, additional, Reuter, Nathalie, additional, Saas, Philippe, additional, Frachet, Philippe, additional, Boulanger, Chantal M., additional, and Witko-Sarsat, Véronique, additional

Published
2016
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42. How Pb2+Binds and Modulates Properties of Ca2+-Signaling Proteins

Author

Dudev, Todor, Grauffel, Cédric, and Lim, Carmay

Abstract

Abiogenic lead (Pb2+), present in the environment in elevated levels due to human activities, has detrimental effects on human health. Metal-binding sites in proteins have been identified as primary targets for lead substitution resulting in malfunction of the host protein. Although Pb2+is known to be a potent competitor of Ca2+in protein binding sites, why/how Pb2+can compete with Ca2+in proteins remains unclear, raising multiple outstanding questions, including the following: (1) What are the physicochemical factors governing the competition between Pb2+and Ca2+? (2) Which Ca2+-binding sites in terms of the structure, composition, overall charge, flexibility, and solvent exposure are the most likely targets for Pb2+attack? Using density functional theory combined with polarizable continuum model calculations, we address these questions by studying the thermodynamic outcome of the competition between Pb2+and Ca2+in various model Ca2+-binding sites, including those modeling voltage-gated calcium channel selectivity filters and EF-hand and non-EF-hand Ca2+-binding sites. The results, which are in good agreement with experiment, reveal that the metal site’s flexibility and number of amino acid ligands dictate the outcome of the competition between Pb2+and Ca2+: If the Ca2+-binding site is relatively rigid and crowded with protein ligands, then Pb2+, upon binding, preserves the native metal-binding site geometry and at low concentrations, can act as an activator of the host protein. If the Ca2+-binding site is flexible and consists of only a few protein ligands, then Pb2+can displace Ca2+and deform the native metal-binding site geometry, resulting in protein malfunction.

Published
2018
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