The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Hannah Gelman - One of the best experts on this subject based on the ideXlab platform.
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a combined approach reveals a Regulatory Mechanism coupling src s kinase activity localization and phosphotransferase independent functions
Molecular Cell, 2019Co-Authors: Ethan Ahler, Ames C Register, Sujata Chakraborty, Linglan Fang, Emily M Dieter, Katherine A Sitko, Rama Subba Rao Vidadala, Bridget M Trevillian, Martin Golkowski, Hannah GelmanAbstract:Multiple layers of regulation modulate the activity and localization of protein kinases. However, many details of kinase regulation remain incompletely understood. Here, we apply saturation mutagenesis and a chemical genetic method for allosterically modulating kinase global conformation to Src kinase, providing insight into known Regulatory Mechanisms and revealing a previously undiscovered interaction between Src's SH4 and catalytic domains. Abrogation of this interaction increased phosphotransferase activity, promoted membrane association, and provoked phosphotransferase-independent alterations in cell morphology. Thus, Src's SH4 domain serves as an intramolecular regulator coupling catalytic activity, global conformation, and localization, as well as mediating a phosphotransferase-independent function. Sequence conservation suggests that the SH4 domain Regulatory interaction exists in other Src-family kinases. Our combined approach's ability to reveal a Regulatory Mechanism in one of the best-studied kinases suggests that it could be applied broadly to provide insight into kinase structure, regulation, and function.
George Q Daley - One of the best experts on this subject based on the ideXlab platform.
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signaling through rna binding proteins as a cell fate Regulatory Mechanism
Cell Cycle, 2017Co-Authors: Kaloyan M Tsanov, George Q DaleyAbstract:Cell identity is controlled by complex gene Regulatory networks that are subject to intricately orchestrated Regulatory Mechanisms.1 Signaling pathways are the master choreographers of these networ...
Jianping Ding - One of the best experts on this subject based on the ideXlab platform.
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structures of human cytosolic nadp dependent isocitrate dehydrogenase reveal a novel self Regulatory Mechanism of activity
Journal of Biological Chemistry, 2004Co-Authors: Jingyue Zhao, Baozhen Peng, Qiuhua Huang, Eddy Arnold, Jianping DingAbstract:Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate, and regulation of the enzymatic activity of IDHs is crucial for their biological functions. Bacterial IDHs are reversibly regulated by phosphorylation of a strictly conserved serine residue at the active site. Eukaryotic NADP-dependent IDHs (NADP-IDHs) have been shown to have diverse important biological functions; however, their Regulatory Mechanism remains unclear. Structural studies of human cytosolic NADP-IDH (HcIDH) in complex with NADP and in complex with NADP, isocitrate, and Ca2+ reveal three biologically relevant conformational states of the enzyme that differ substantially in the structure of the active site and in the overall structure. A structural segment at the active site that forms a conserved α-helix in all known NADP-IDH structures assumes a loop conformation in the open, inactive form of HcIDH; a partially unraveled α-helix in the semi-open, intermediate form; and an α-helix in the closed, active form. The side chain of Asp279 of this segment occupies the isocitrate-binding site and forms hydrogen bonds with Ser94 (the equivalent of the phosphorylation site in bacterial IDHs) in the inactive form and chelates the metal ion in the active form. The structural data led us to propose a novel self-Regulatory Mechanism for HcIDH that mimics the phosphorylation Mechanism used by the bacterial homologs, consistent with biochemical and biological data. This Mechanism might be applicable to other eukaryotic NADP-IDHs. The results also provide insights into the recognition and specificity of substrate and cofactor by eukaryotic NADP-IDHs.
Ethan Ahler - One of the best experts on this subject based on the ideXlab platform.
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a combined approach reveals a Regulatory Mechanism coupling src s kinase activity localization and phosphotransferase independent functions
Molecular Cell, 2019Co-Authors: Ethan Ahler, Ames C Register, Sujata Chakraborty, Linglan Fang, Emily M Dieter, Katherine A Sitko, Rama Subba Rao Vidadala, Bridget M Trevillian, Martin Golkowski, Hannah GelmanAbstract:Multiple layers of regulation modulate the activity and localization of protein kinases. However, many details of kinase regulation remain incompletely understood. Here, we apply saturation mutagenesis and a chemical genetic method for allosterically modulating kinase global conformation to Src kinase, providing insight into known Regulatory Mechanisms and revealing a previously undiscovered interaction between Src's SH4 and catalytic domains. Abrogation of this interaction increased phosphotransferase activity, promoted membrane association, and provoked phosphotransferase-independent alterations in cell morphology. Thus, Src's SH4 domain serves as an intramolecular regulator coupling catalytic activity, global conformation, and localization, as well as mediating a phosphotransferase-independent function. Sequence conservation suggests that the SH4 domain Regulatory interaction exists in other Src-family kinases. Our combined approach's ability to reveal a Regulatory Mechanism in one of the best-studied kinases suggests that it could be applied broadly to provide insight into kinase structure, regulation, and function.
Ryuhei Okuyama - One of the best experts on this subject based on the ideXlab platform.
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high commitment of embryonic keratinocytes to terminal differentiation through a notch1 caspase 3 Regulatory Mechanism
Developmental Cell, 2004Co-Authors: Ryuhei Okuyama, Bach Cuc Nguyen, Claudio Talora, Eisaku Ogawa, Alice Tommasi Di Vignano, Maria Lioumi, Giovanna Chiorino, Hachiro Tagami, Minna WooAbstract:Abstract Embryonic cells are expected to possess high growth/differentiation potential, required for organ morphogenesis and expansion during development. However, little is known about the intrinsic properties of embryonic epithelial cells due to difficulties in their isolation and cultivation. We report here that pure keratinocyte populations from E15.5 mouse embryos commit irreversibly to differentiation much earlier than newborn cells. Notch signaling, which promotes keratinocyte differentiation, is upregulated in embryonic keratinocyte and epidermis, and elevated caspase 3 expression, which we identify as a transcriptional Notch1 target, accounts in part for the high commitment of embryonic keratinocytes to terminal differentiation. In vivo, lack of caspase 3 results in increased proliferation and decreased differentiation of interfollicular embryonic keratinocytes, together with decreased activation of PKC-δ, a caspase 3 substrate which functions as a positive regulator of keratinocyte differentiation. Thus, a Notch1-caspase 3 Regulatory Mechanism underlies the intrinsically high commitment of embryonic keratinocytes to terminal differentiation.
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high commitment of embryonic keratinocytes to terminal differentiation through a notch1 caspase 3 Regulatory Mechanism
Developmental Cell, 2004Co-Authors: Ryuhei Okuyama, Bach Cuc Nguyen, Claudio Talora, Eisaku Ogawa, Alice Tommasi Di Vignano, Maria Lioumi, Giovanna Chiorino, Hachiro Tagami, Minna Woo, Paolo G DottoAbstract:Embryonic cells are expected to possess high growth/differentiation potential, required for organ morphogenesis and expansion during development. However, little is known about the intrinsic properties of embryonic epithelial cells due to difficulties in their isolation and cultivation. We report here that pure keratinocyte populations from E15.5 mouse embryos commit irreversibly to differentiation much earlier than newborn cells. Notch signaling, which promotes keratinocyte differentiation, is upregulated in embryonic keratinocyte and epidermis, and elevated caspase 3 expression, which we identify as a transcriptional Notch1 target, accounts in part for the high commitment of embryonic keratinocytes to terminal differentiation. In vivo, lack of caspase 3 results in increased proliferation and decreased differentiation of interfollicular embryonic keratinocytes, together with decreased activation of PKC-delta, a caspase 3 substrate which functions as a positive regulator of keratinocyte differentiation. Thus, a Notch1-caspase 3 Regulatory Mechanism underlies the intrinsically high commitment of embryonic keratinocytes to terminal differentiation.
