The Experts below are selected from a list of 1842 Experts worldwide ranked by ideXlab platform
Thierry Frebourg - One of the best experts on this subject based on the ideXlab platform.
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The Rapp–Hodgkin syndrome results from mutations of the TP63 gene
European Journal of Human Genetics, 2003Co-Authors: Gaëlle Bougeard, Smail Hadj-rabia, Laurence Faivre, Nasrin Sarafan-vasseur, Thierry FrebourgAbstract:The Rapp-Hodgkin syndrome (RHS, MIM 129400) corresponds to a rare form of anhydrotic ectodermal dysplasia, which shares some features with the ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC, MIM 604292) resulting from TP63 mutations. We report here, in two unrelated patients with RHS, the identification of two distinct TP63 mutations, corresponding to a novel frameshift mutation (1709DelA, exon 14) located downstream the Sterile Alpha Motif (SAM) domain and to a missense mutation (R279H, exon 7) within the DNA binding domain. Functional analysis of the R279H mutation, which had previously been reported in several EEC families, shows that this mutation disrupted the dominant negative activity of the DeltaNp63Alpha and gamma isoforms on the transcriptional activity of TP53. This report shows, on a molecular basis, that RHS is also an EEC-like syndrome resulting from mutations of the TP63 gene, and highlights the wide phenotypic spectrum associated to TP63 mutations.
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The Rapp–Hodgkin syndrome results from mutations of the TP63 gene
European Journal of Human Genetics, 2003Co-Authors: Gaëlle Bougeard, Smail Hadj-rabia, Laurence Faivre, Nasrin Sarafan-vasseur, Thierry FrebourgAbstract:The Rapp–Hodgkin syndrome (RHS, MIM 129400) corresponds to a rare form of anhydrotic ectodermal dysplasia, which shares some features with the ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC, MIM 604292) resulting from TP63 mutations. We report here, in two unrelated patients with RHS, the identification of two distinct TP63 mutations, corresponding to a novel frameshift mutation (1709DelA, exon 14) located downstream the Sterile Alpha Motif (SAM) domain and to a missense mutation (R279H, exon 7) within the DNA binding domain. Functional analysis of the R279H mutation, which had previously been reported in several EEC families, shows that this mutation disrupted the dominant negative activity of the ΔNp63 α and γ isoforms on the transcriptional activity of TP53. This report shows, on a molecular basis, that RHS is also an EEC-like syndrome resulting from mutations of the TP63 gene, and highlights the wide phenotypic spectrum associated to TP63 mutations.
James U. Bowie - One of the best experts on this subject based on the ideXlab platform.
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a human Sterile Alpha Motif domain polymerizome
Protein Science, 2011Co-Authors: Mary Jane Knight, Catherine Leettola, Mari Gingery, James U. BowieAbstract:The Sterile Alpha Motif (SAM) domain is one of the most common protein modules found in eukaryotic genomes. Many SAM domains have been shown to form helical polymer structures suggesting that SAM modules can be used to create large protein complexes in the cell. Because many polymeric SAM domains form heterogenous and insoluble aggregates that are experimentally intractable when isolated, it is likely that many polymeric SAM domains have gone uncharacterized. We, therefore, developed a method to maintain polymeric SAM domains in a soluble form that allowed rapid screening for potential SAM polymers. SAM domains were expressed as fusions to a super-negatively charged green fluorescent protein (negGFP). The negGFP imparts three useful properties to the SAM domains: (1) the charge helps to maintain solubility; (2) the charge leads to reliable migration toward the cathode on native gels; and (3) the fluorescence emission allows visualization in crude extracts. Using the negGFP-SAM fusions, we screened a large library of human SAM domains for polymerization using a native gel screen. A selected set of hSAM domains were then purified and examined for true polymer formation by electron microscopy. In this manner, we identified a set of new potential SAM polymers: ANKS3, Atherin, BicaudalC1, Caskin1, Caskin2, Kazrin, L3MBTL3, L3MBTL4, LBP, LiprinB1, LiprinB2, SAMD8, SAMD9, and STIM2. While further characterization will be necessary to verify that the SAM domains identified here truly form polymers, our results provide a much stronger working hypothesis for a large number of proteins that was possible from sequence analysis alone.
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Identifying polymer‐forming SAM domains
Proteins, 2009Co-Authors: Alejandro D. Meruelo, James U. BowieAbstract:Sterile Alpha Motif (SAM) domains are common protein modules in eukaryotic cells. It has not been possible to assign functions to uncharacterized SAM domains because they have been found to participate in diverse functions ranging from protein-protein interactions to RNA binding. Here we computationally identify likely members of the subclass of SAM domains that form polymers. Sequences were virtually threaded onto known polymer structures and then evaluated for compatibility with the polymer. We find that known SAM polymers score better than the vast majority of known non-polymers: 100% (7 of 7) of known polymers and only 8% of known non-polymers (1 of 12) score above a defined threshold value. Of 2901 SAM family members, we find 694 that score above the threshold and are likely polymers, including SAM domains from the proteins Lethal Malignant Brain Tumor, Bicaudal-C, Liprin-β, Adenylate Cyclase and Atherin.
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Identifying polymer-forming SAM domains.
Proteins, 2008Co-Authors: Alejandro D. Meruelo, James U. BowieAbstract:Sterile Alpha Motif (SAM) domains are common protein modules in eukaryotic cells. It has not been possible to assign functions to uncharacterized SAM domains because they have been found to participate in diverse functions ranging from protein-protein interactions to RNA binding. Here we computationally identify likely members of the subclass of SAM domains that form polymers. Sequences were virtually threaded onto known polymer structures and then evaluated for compatibility with the polymer. We find that known SAM polymers score better than the vast majority of known non-polymers: 100% (7 of 7) of known polymers and only 8% of known non-polymers (1 of 12) score above a defined threshold value. Of 2901 SAM family members, we find 694 that score above the threshold and are likely polymers, including SAM domains from the proteins Lethal Malignant Brain Tumor, Bicaudal-C, Liprin-β, Adenylate Cyclase and Atherin.
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an architectural framework that may lie at the core of the postsynaptic density
Science, 2006Co-Authors: Marisa K Baron, Tobias M. Boeckers, Eckart D Gundelfinger, Mari Gingery, Salem Faham, Bianca Vaida, Michael R Sawaya, Danielle Salyer, James U. BowieAbstract:The postsynaptic density (PSD) is a complex assembly of proteins associated with the postsynaptic membrane that organizes neurotransmitter receptors, signaling pathways, and regulatory elements within a cytoskeletal matrix. Here we show that the Sterile Alpha Motif domain of rat Shank3/ProSAP2, a master scaffolding protein located deep within the PSD, can form large sheets composed of helical fibers stacked side by side. Zn2+, which is found in high concentrations in the PSD, binds tightly to Shank3 and may regulate assembly. Sheets of the Shank protein could form a platform for the construction of the PSD complex.
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sam domains uniform structure diversity of function
Trends in Biochemical Sciences, 2003Co-Authors: Chongwoo A Kim, James U. BowieAbstract:Abstract Sterile Alpha Motif (SAM) domains are known to exhibit diverse protein–protein interaction modes. They can form multiple self-association architectures and also bind to various non-SAM domain-containing proteins. Surprising new work adds a completely unanticipated function for some SAM domains – the ability to bind RNA. Such functional diversity within a homologous protein family presents a significant challenge for bioinformatic function assignment.
Chih Yang Huang - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and structure activity relationships of 1 2 3 triazole benzenesulfonamides as new selective leucine zipper and Sterile Alpha Motif kinase zak inhibitors
Journal of Medicinal Chemistry, 2020Co-Authors: Jianzhang Yang, Marthandam Asokan Shibu, Lulu Kong, Jinfeng Luo, Farheen Badrealamkhan, Yanhui Huang, Caihong Yun, Chih Yang HuangAbstract:ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.
Chris Dardick - One of the best experts on this subject based on the ideXlab platform.
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loss of a highly conserved Sterile Alpha Motif domain gene weep results in pendulous branch growth in peach trees
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Courtney A. Hollender, Thierry Pascal, Amy Tabb, Toto Hadiarto, Chinnathambi Srinivasan, Wanpeng Wang, Zhongchi Liu, Ralph Scorza, Chris DardickAbstract:Plant shoots typically grow upward in opposition to the pull of gravity. However, exceptions exist throughout the plant kingdom. Most conspicuous are trees with weeping or pendulous branches. While such trees have long been cultivated and appreciated for their ornamental value, the molecular basis behind the weeping habit is not known. Here, we characterized a weeping tree phenotype in Prunus persica (peach) and identified the underlying genetic mutation using a genomic sequencing approach. Weeping peach tree shoots exhibited a downward elliptical growth pattern and did not exhibit an upward bending in response to 90° reorientation. The causative allele was found to be an uncharacterized gene, Ppa013325, having a 1.8-Kb deletion spanning the 5' end. This gene, dubbed WEEP, was predominantly expressed in phloem tissues and encodes a highly conserved 129-amino acid protein containing a Sterile Alpha Motif (SAM) domain. Silencing WEEP in the related tree species Prunus domestica (plum) resulted in more outward, downward, and wandering shoot orientations compared to standard trees, supporting a role for WEEP in directing lateral shoot growth in trees. This previously unknown regulator of branch orientation, which may also be a regulator of gravity perception or response, provides insights into our understanding of how tree branches grow in opposition to gravity and could serve as a critical target for manipulating tree architecture for improved tree shape in agricultural and horticulture applications.
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Loss of a highly conserved Sterile Alpha Motif domain gene (WEEP) results in pendulous branch growth in peach trees
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Courtney A. Hollender, Thierry Pascal, Amy Tabb, Toto Hadiarto, Chinnathambi Srinivasan, Wanpeng Wang, Zhongchi Liu, Ralph Scorza, Chris DardickAbstract:Plant shoots typically grow upward in opposition to the pull of gravity. However, exceptions exist throughout the plant kingdom. Most conspicuous are trees with weeping or pendulous branches. While such trees have long been cultivated and appreciated for their ornamental value, the molecular basis behind the weeping habit is not known. Here, we characterized a weeping tree phenotype in Prunus persica (peach) and identified the underlying genetic mutation using a genomic sequencing approach. Weeping peach tree shoots exhibited a downward elliptical growth pattern and did not exhibit an upward bending in response to 90 degrees reorientation. The causative allele was found to be an uncharacterized gene, Ppa013325, having a 1.8-Kb deletion spanning the 5' end. This gene, dubbed WEEP, was predominantly expressed in phloem tissues and encodes a highly conserved 129-amino acid protein containing a Sterile Alpha Motif (SAM) domain. Silencing WEEP in the related tree species Prunus domestica (plum) resulted in more outward, downward, and wandering shoot orientations compared to standard trees, supporting a role for WEEP in directing lateral shoot growth in trees. This previously unknown regulator of branch orientation, which may also be a regulator of gravity perception or response, provides insights into our understanding of how tree branches grow in opposition to gravity and could serve as a critical target for manipulating tree architecture for improved tree shape in agricultural and horticulture applications.
Jose L Neira - One of the best experts on this subject based on the ideXlab platform.
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trifluoroethanol induced conformational transition of the c terminal Sterile Alpha Motif sam of human p73
Archives of Biochemistry and Biophysics, 2017Co-Authors: Jose L Neira, Ana CamaraartigasAbstract:The Alpha splice variant of p73 (p73α), a homologue of the tumour suppressor p53, has at its C terminus a Sterile Alpha Motif (SAM); this domain, SAMp73, is involved in lipid binding and it is thought to mediate in protein-protein interactions. As SAMp73 is a 68-residue-long helical bundle, it could be a good model to study the (2,2,2-trifluoroethanol) TFE-induced conformational transitions of α-helical proteins. Furthermore, as SAMp73 binds to lipids through a well-known polypeptide patch, we can test whether TFE is a good mimic of lipids and membranes. To address those questions, we used several biophysical probes, namely, fluorescence, circular dichroism, 1D, 2D and 3D-NMR spectroscopies, and dynamic light scattering. The TFE-induced conformational transition of SAMp73 was complex, involving several species as detected by the biophysical probes. The last TFE-induced transition occurred at a concentration of TFE of ∼20% (v/v), where the protein lost its compactness. None of those TFE-induced species accumulated during the two-state folding of SAMp73 in aqueous solution. The final state at 40% TFE was highly helical, but its structure was not rigid. For SAMp73, TFE did not properly mimic a membrane-like environment, since at very low TFE concentrations, other residues, together with those known to interact with lipids, were also affected by the co-solvent. Comparison with studies on isolated peptides, comprising the helical regions of SAMp73, suggests that peptides were good models of the intact protein in TFE.
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structural dissection of the c terminal Sterile Alpha Motif sam of human p73
Archives of Biochemistry and Biophysics, 2014Co-Authors: Jose L NeiraAbstract:The Alpha splice variant of p73 (p73α), a homologue of the tumour suppressor p53, has at its C terminus a Sterile Alpha Motif (SAM); this domain, SAMp73, is involved in lipid binding and it is thought to mediate in protein-protein interactions. SAMp73 is composed of five helices (α1-α5). In this work, we dissected SAMp73 in fragments encompassing the different helices, to study the conformational stability of the isolated elements of secondary structure. There was no evidence of stable residual helical structure in the isolated α1, α4 and α5 helices in aqueous solution, as shown by 2D-(1)H NMR and far-UV CD spectroscopies; those helices acquired native-like helical structure in the presence of 40% trifluoroethanol (TFE). The population of helical structure in α5 seemed to be driven by the indole moiety of Trp542, and it was enhanced by the presence of α4. On the other hand, helices α2 and 310(α3) had a tendency to self-associate even in TFE-water solutions. However, the short, aggregation-prone 310(α3) helix was key to attain the native-like fold of SAMp73, as suggested by experiments with non-covalent complexes among the peptides.
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the c terminal Sterile Alpha Motif sam domain of human p73 is a highly dynamic protein which acquires high thermal stability through a decrease in backbone flexibility
Physical Chemistry Chemical Physics, 2012Co-Authors: Jose L Neira, Paz Sevilla, Francisco GarciablancoAbstract:The α-splice variant of p73 (p73α), a homologue of the tumour suppressor p53, has close to its C terminus a Sterile Alpha Motif (SAM), SAMp73, that is involved in protein–biomolecule interactions. The conformational stability of SAMp73 is low (∼5 kcal mol−1), although its thermal stability is high. To explain this high thermostability, we studied the dynamics of SAMp73 over a wide range of GdmCl (guanidine hydrochloride) concentrations and temperatures by NMR relaxation, NMR hydrogen-exchange (HX) and fluorescence lifetime approaches. The slowest exchanging residues of SAMp73 belong to the helical regions, and they did exchange by a global unfolding process. Moreover, SAMp73 was very flexible, with most of its amide protons affected by slow μs–ms conformational exchange. Within this time scale, the residues of SAMp73 with the largest exchange rates (Rex) were involved in binding with other molecules; therefore, the flexibility in the μs–ms range was associated with biological functions. As the [GdmCl] increased, the pico-to-nanosecond flexibility of the backbone amide protons raised, but it did so differently depending on the residue. We were able to obtain, for the first time, the linear [GdmCl]-variation of the local conformational entropies, mSi, which ranged from 5.3 to 0.3 cal mol−1 K−1 M−1, similar to those measured by using macroscopic techniques in other proteins. Conversely, the temperature dependence of the pico-to-nanosecond dynamics of the backbone amide protons of SAMp73 indicates that the flexibility of some residues decreased with the temperature; these results explain the high thermostability of the protein.
