The Experts below are selected from a list of 5583 Experts worldwide ranked by ideXlab platform
Kentaro Takayama - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of peptidic partial agonists of human neuromedin u receptor 1 with enhanced serum stability
Bioorganic & Medicinal Chemistry Letters, 2020Co-Authors: Kentaro Takayama, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Tomo Asari, Yu Sasaki, Mikiya MiyazatoAbstract:Abstract Neuromedin U (NMU) activates two receptors (NMUR1 and NMUR2) and is a promising candidate for development of drugs to combat obesity. Previously, we obtained Hexapeptides as selective full NMUR agonists. Development of a partial agonist which mildly activates receptors is an effective strategy which lead to an understanding of the functions of NMU receptors. In 2014, we reported Hexapeptide 3 (CPN-124) as an NMUR1-selective partial agonist but its selectivity and serum stability were unsatisfactory. Herein, we report the development of a Hexapeptide-type partial agonist (8, CPN-223) based on a peptide (3) but with higher NMUR1-selectivity and enhanced serum stability. A structure-activity relationship study of synthetic pentapeptide derivatives suggested that a Hexapeptide is a minimum structure consistent with both good NMUR1-selective agonistic activity and serum stability.
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discovery of a human neuromedin u receptor 1 selective Hexapeptide agonist with enhanced serum stability
Journal of Medicinal Chemistry, 2017Co-Authors: Kentaro Takayama, Miwa Mori, Akiko Tanaka, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Toshiyasu Sakane, Akira YamamotoAbstract:Neuromedin U (NMU) activates two NMU receptors (NMUR1 and NMUR2) and is a useful antiobesity drug lead. We report discovery of a Hexapeptide agonist, 2-thienylacetyl-Trp1-Phe(4-F)2-Arg3-Pro4-Arg5-Asn6-NH2 (4). However, the NMUR1 selectivity and serum stability of this agonist were unsatisfactory. Through a structure–activity relationship study focused on residue 2 of agonist 4, serum stability, and pharmacokinetic properties, we report here the discovery of a novel NMUR1 selective Hexapeptide agonist 7b that suppresses body weight gain in mice.
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Discovery of a Human Neuromedin U Receptor 1‑Selective Hexapeptide Agonist with Enhanced Serum Stability
2017Co-Authors: Kentaro Takayama, Miwa Mori, Akiko Tanaka, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Toshiyasu Sakane, Akira YamamotoAbstract:Neuromedin U (NMU) activates two NMU receptors (NMUR1 and NMUR2) and is a useful antiobesity drug lead. We report discovery of a Hexapeptide agonist, 2-thienylacetyl-Trp1-Phe(4-F)2-Arg3-Pro4-Arg5-Asn6-NH2 (4). However, the NMUR1 selectivity and serum stability of this agonist were unsatisfactory. Through a structure–activity relationship study focused on residue 2 of agonist 4, serum stability, and pharmacokinetic properties, we report here the discovery of a novel NMUR1 selective Hexapeptide agonist 7b that suppresses body weight gain in mice
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discovery of selective Hexapeptide agonists to human neuromedin u receptors types 1 and 2
Journal of Medicinal Chemistry, 2014Co-Authors: Kentaro Takayama, Akihiro Taguchi, Kenji Mori, Mikiya Miyazato, Koji Taketa, Fumika Yakushiji, Naoto Minamino, Kenji Kangawa, Yoshio HayashiAbstract:Neuromedin U (NMU) are bioactive peptides with a common C-terminal heptapeptide sequence (FLFRPRN-amide, 1a) among mammals, which is responsible for receptor activation, namely NMU receptor types 1 (NMUR1) and 2 (NMUR2). Among the various physiological actions of NMU, the anorexigenic effect has recently attracted attention in drug discovery efforts for treating obesity. Although several structure–activity relationship (SAR) studies have been reported, receptor-selective small peptide agonists have yet to be disclosed. Herein a SAR study of 1a-derived peptide derivatives is described. We initially screened both human NMUR1- and NMUR2-selective peptides in calcium-mobilization assays with cells transiently expressing receptors. Then we performed a precise assay with a stable expression system of receptors and consequently discovered Hexapeptides 8d and 6b possessing selective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significant NMUR1 activa...
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discovery of selective Hexapeptide agonists to human neuromedin u receptors types 1 and 2
Journal of Medicinal Chemistry, 2014Co-Authors: Kentaro Takayama, Akihiro Taguchi, Kenji Mori, Mikiya Miyazato, Koji Taketa, Fumika Yakushiji, Naoto Minamino, Kenji Kangawa, Yoshio HayashiAbstract:Neuromedin U (NMU) are bioactive peptides with a common C-terminal heptapeptide sequence (FLFRPRN-amide, 1a) among mammals, which is responsible for receptor activation, namely NMU receptor types 1 (NMUR1) and 2 (NMUR2). Among the various physiological actions of NMU, the anorexigenic effect has recently attracted attention in drug discovery efforts for treating obesity. Although several structure-activity relationship (SAR) studies have been reported, receptor-selective small peptide agonists have yet to be disclosed. Herein a SAR study of 1a-derived peptide derivatives is described. We initially screened both human NMUR1- and NMUR2-selective peptides in calcium-mobilization assays with cells transiently expressing receptors. Then we performed a precise assay with a stable expression system of receptors and consequently discovered Hexapeptides 8d and 6b possessing selective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significant NMUR1 activation, should aid in the development of anorexigenic drugs as well as advance NMU-related endocrinological research.
David N Cornfield - One of the best experts on this subject based on the ideXlab platform.
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an amyloidogenic Hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis
PLOS ONE, 2018Co-Authors: Sidharth Mahapatra, Lihua Ying, Lawrence Steinman, Michael P Kurnellas, Jonathan B Rothbard, David N CornfieldAbstract:Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of Hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin Hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin Hexapeptide (20 μg) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 hours for 3 days. Levels of pro- (IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-10) cytokines were measured via ELISA at 1, 3, 6, 12, and 24 hours after LPS (i.p.). As a metric of lung injury, pulmonary artery endothelial cell (PAEC) barrier function was tested 24 hours after LPS administration by comparing lung wet-to-dry ratios, Evan's blue dye (EBD) extravasation, lung histology and caspase-3 activity. Compared to controls, pretreatment with amylin Hexapeptide significantly reduced mortality (p<0.05 at 72 h), illness severity (p<0.05), and pro-inflammatory cytokine levels, while IL-10 levels were elevated (p<0.05). Amylin pretreatment attenuated LPS-induced lung injury, as demonstrated by decreased lung water and caspase-3 activity (p<0.05, versus PBS). Hence, in a murine model of systemic inflammation, pretreatment with amylin Hexapeptide reduced mortality, disease severity, and preserved lung barrier function. Amylin Hexapeptide may represent a novel therapeutic tool to mitigate sepsis severity and lung injury.
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an amyloidogenic Hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis
Pediatrics, 2018Co-Authors: Sidharth Mahapatra, Lihua Ying, Lawrence Steinman, David N CornfieldAbstract:Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloidforming fibrils, comprised of Hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin Hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin Hexapeptide (20μg) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 …
Kenji Mori - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of peptidic partial agonists of human neuromedin u receptor 1 with enhanced serum stability
Bioorganic & Medicinal Chemistry Letters, 2020Co-Authors: Kentaro Takayama, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Tomo Asari, Yu Sasaki, Mikiya MiyazatoAbstract:Abstract Neuromedin U (NMU) activates two receptors (NMUR1 and NMUR2) and is a promising candidate for development of drugs to combat obesity. Previously, we obtained Hexapeptides as selective full NMUR agonists. Development of a partial agonist which mildly activates receptors is an effective strategy which lead to an understanding of the functions of NMU receptors. In 2014, we reported Hexapeptide 3 (CPN-124) as an NMUR1-selective partial agonist but its selectivity and serum stability were unsatisfactory. Herein, we report the development of a Hexapeptide-type partial agonist (8, CPN-223) based on a peptide (3) but with higher NMUR1-selectivity and enhanced serum stability. A structure-activity relationship study of synthetic pentapeptide derivatives suggested that a Hexapeptide is a minimum structure consistent with both good NMUR1-selective agonistic activity and serum stability.
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discovery of a human neuromedin u receptor 1 selective Hexapeptide agonist with enhanced serum stability
Journal of Medicinal Chemistry, 2017Co-Authors: Kentaro Takayama, Miwa Mori, Akiko Tanaka, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Toshiyasu Sakane, Akira YamamotoAbstract:Neuromedin U (NMU) activates two NMU receptors (NMUR1 and NMUR2) and is a useful antiobesity drug lead. We report discovery of a Hexapeptide agonist, 2-thienylacetyl-Trp1-Phe(4-F)2-Arg3-Pro4-Arg5-Asn6-NH2 (4). However, the NMUR1 selectivity and serum stability of this agonist were unsatisfactory. Through a structure–activity relationship study focused on residue 2 of agonist 4, serum stability, and pharmacokinetic properties, we report here the discovery of a novel NMUR1 selective Hexapeptide agonist 7b that suppresses body weight gain in mice.
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Discovery of a Human Neuromedin U Receptor 1‑Selective Hexapeptide Agonist with Enhanced Serum Stability
2017Co-Authors: Kentaro Takayama, Miwa Mori, Akiko Tanaka, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Toshiyasu Sakane, Akira YamamotoAbstract:Neuromedin U (NMU) activates two NMU receptors (NMUR1 and NMUR2) and is a useful antiobesity drug lead. We report discovery of a Hexapeptide agonist, 2-thienylacetyl-Trp1-Phe(4-F)2-Arg3-Pro4-Arg5-Asn6-NH2 (4). However, the NMUR1 selectivity and serum stability of this agonist were unsatisfactory. Through a structure–activity relationship study focused on residue 2 of agonist 4, serum stability, and pharmacokinetic properties, we report here the discovery of a novel NMUR1 selective Hexapeptide agonist 7b that suppresses body weight gain in mice
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discovery of selective Hexapeptide agonists to human neuromedin u receptors types 1 and 2
Journal of Medicinal Chemistry, 2014Co-Authors: Kentaro Takayama, Akihiro Taguchi, Kenji Mori, Mikiya Miyazato, Koji Taketa, Fumika Yakushiji, Naoto Minamino, Kenji Kangawa, Yoshio HayashiAbstract:Neuromedin U (NMU) are bioactive peptides with a common C-terminal heptapeptide sequence (FLFRPRN-amide, 1a) among mammals, which is responsible for receptor activation, namely NMU receptor types 1 (NMUR1) and 2 (NMUR2). Among the various physiological actions of NMU, the anorexigenic effect has recently attracted attention in drug discovery efforts for treating obesity. Although several structure–activity relationship (SAR) studies have been reported, receptor-selective small peptide agonists have yet to be disclosed. Herein a SAR study of 1a-derived peptide derivatives is described. We initially screened both human NMUR1- and NMUR2-selective peptides in calcium-mobilization assays with cells transiently expressing receptors. Then we performed a precise assay with a stable expression system of receptors and consequently discovered Hexapeptides 8d and 6b possessing selective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significant NMUR1 activa...
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discovery of selective Hexapeptide agonists to human neuromedin u receptors types 1 and 2
Journal of Medicinal Chemistry, 2014Co-Authors: Kentaro Takayama, Akihiro Taguchi, Kenji Mori, Mikiya Miyazato, Koji Taketa, Fumika Yakushiji, Naoto Minamino, Kenji Kangawa, Yoshio HayashiAbstract:Neuromedin U (NMU) are bioactive peptides with a common C-terminal heptapeptide sequence (FLFRPRN-amide, 1a) among mammals, which is responsible for receptor activation, namely NMU receptor types 1 (NMUR1) and 2 (NMUR2). Among the various physiological actions of NMU, the anorexigenic effect has recently attracted attention in drug discovery efforts for treating obesity. Although several structure-activity relationship (SAR) studies have been reported, receptor-selective small peptide agonists have yet to be disclosed. Herein a SAR study of 1a-derived peptide derivatives is described. We initially screened both human NMUR1- and NMUR2-selective peptides in calcium-mobilization assays with cells transiently expressing receptors. Then we performed a precise assay with a stable expression system of receptors and consequently discovered Hexapeptides 8d and 6b possessing selective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significant NMUR1 activation, should aid in the development of anorexigenic drugs as well as advance NMU-related endocrinological research.
Akihiro Taguchi - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of peptidic partial agonists of human neuromedin u receptor 1 with enhanced serum stability
Bioorganic & Medicinal Chemistry Letters, 2020Co-Authors: Kentaro Takayama, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Tomo Asari, Yu Sasaki, Mikiya MiyazatoAbstract:Abstract Neuromedin U (NMU) activates two receptors (NMUR1 and NMUR2) and is a promising candidate for development of drugs to combat obesity. Previously, we obtained Hexapeptides as selective full NMUR agonists. Development of a partial agonist which mildly activates receptors is an effective strategy which lead to an understanding of the functions of NMU receptors. In 2014, we reported Hexapeptide 3 (CPN-124) as an NMUR1-selective partial agonist but its selectivity and serum stability were unsatisfactory. Herein, we report the development of a Hexapeptide-type partial agonist (8, CPN-223) based on a peptide (3) but with higher NMUR1-selectivity and enhanced serum stability. A structure-activity relationship study of synthetic pentapeptide derivatives suggested that a Hexapeptide is a minimum structure consistent with both good NMUR1-selective agonistic activity and serum stability.
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discovery of a human neuromedin u receptor 1 selective Hexapeptide agonist with enhanced serum stability
Journal of Medicinal Chemistry, 2017Co-Authors: Kentaro Takayama, Miwa Mori, Akiko Tanaka, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Toshiyasu Sakane, Akira YamamotoAbstract:Neuromedin U (NMU) activates two NMU receptors (NMUR1 and NMUR2) and is a useful antiobesity drug lead. We report discovery of a Hexapeptide agonist, 2-thienylacetyl-Trp1-Phe(4-F)2-Arg3-Pro4-Arg5-Asn6-NH2 (4). However, the NMUR1 selectivity and serum stability of this agonist were unsatisfactory. Through a structure–activity relationship study focused on residue 2 of agonist 4, serum stability, and pharmacokinetic properties, we report here the discovery of a novel NMUR1 selective Hexapeptide agonist 7b that suppresses body weight gain in mice.
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Discovery of a Human Neuromedin U Receptor 1‑Selective Hexapeptide Agonist with Enhanced Serum Stability
2017Co-Authors: Kentaro Takayama, Miwa Mori, Akiko Tanaka, Erina Nomura, Yuko Sohma, Akihiro Taguchi, Atsuhiko Taniguchi, Kenji Mori, Toshiyasu Sakane, Akira YamamotoAbstract:Neuromedin U (NMU) activates two NMU receptors (NMUR1 and NMUR2) and is a useful antiobesity drug lead. We report discovery of a Hexapeptide agonist, 2-thienylacetyl-Trp1-Phe(4-F)2-Arg3-Pro4-Arg5-Asn6-NH2 (4). However, the NMUR1 selectivity and serum stability of this agonist were unsatisfactory. Through a structure–activity relationship study focused on residue 2 of agonist 4, serum stability, and pharmacokinetic properties, we report here the discovery of a novel NMUR1 selective Hexapeptide agonist 7b that suppresses body weight gain in mice
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discovery of selective Hexapeptide agonists to human neuromedin u receptors types 1 and 2
Journal of Medicinal Chemistry, 2014Co-Authors: Kentaro Takayama, Akihiro Taguchi, Kenji Mori, Mikiya Miyazato, Koji Taketa, Fumika Yakushiji, Naoto Minamino, Kenji Kangawa, Yoshio HayashiAbstract:Neuromedin U (NMU) are bioactive peptides with a common C-terminal heptapeptide sequence (FLFRPRN-amide, 1a) among mammals, which is responsible for receptor activation, namely NMU receptor types 1 (NMUR1) and 2 (NMUR2). Among the various physiological actions of NMU, the anorexigenic effect has recently attracted attention in drug discovery efforts for treating obesity. Although several structure–activity relationship (SAR) studies have been reported, receptor-selective small peptide agonists have yet to be disclosed. Herein a SAR study of 1a-derived peptide derivatives is described. We initially screened both human NMUR1- and NMUR2-selective peptides in calcium-mobilization assays with cells transiently expressing receptors. Then we performed a precise assay with a stable expression system of receptors and consequently discovered Hexapeptides 8d and 6b possessing selective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significant NMUR1 activa...
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discovery of selective Hexapeptide agonists to human neuromedin u receptors types 1 and 2
Journal of Medicinal Chemistry, 2014Co-Authors: Kentaro Takayama, Akihiro Taguchi, Kenji Mori, Mikiya Miyazato, Koji Taketa, Fumika Yakushiji, Naoto Minamino, Kenji Kangawa, Yoshio HayashiAbstract:Neuromedin U (NMU) are bioactive peptides with a common C-terminal heptapeptide sequence (FLFRPRN-amide, 1a) among mammals, which is responsible for receptor activation, namely NMU receptor types 1 (NMUR1) and 2 (NMUR2). Among the various physiological actions of NMU, the anorexigenic effect has recently attracted attention in drug discovery efforts for treating obesity. Although several structure-activity relationship (SAR) studies have been reported, receptor-selective small peptide agonists have yet to be disclosed. Herein a SAR study of 1a-derived peptide derivatives is described. We initially screened both human NMUR1- and NMUR2-selective peptides in calcium-mobilization assays with cells transiently expressing receptors. Then we performed a precise assay with a stable expression system of receptors and consequently discovered Hexapeptides 8d and 6b possessing selective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significant NMUR1 activation, should aid in the development of anorexigenic drugs as well as advance NMU-related endocrinological research.
Eva-maria Mandelkow - One of the best experts on this subject based on the ideXlab platform.
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tau aggregation is driven by a transition from random coil to beta sheet structure
Biochimica et Biophysica Acta, 2005Co-Authors: Martin Von Bergen, Stefan Barghorn, Jacek Biernat, Eva-maria MandelkowAbstract:The abnormal aggregation of the microtubule associated protein tau into paired helical filaments (PHFs) is one the hallmarks of Alzheimer's disease. The soluble protein is one of the longest natively unfolded proteins, lacking significant amounts of secondary structure over a sequence of 441 amino acids in the longest isoform. Furthermore, the unfolded character is consistent with some notable features of the protein like stability towards heat and acid treatment. It is still unclear how these characteristics support the physiological function of binding to and stabilization of microtubules. We review here some recent studies on how an unfolded protein such as tau can adopt β-structure, which then leads to the highly ordered morphology of the PHFs. The core sequence for both microtubule binding and PHF formation is the microtubule binding domain containing three or four repeats. This region alone is sufficient for PHF formation and mostly unfolded in the soluble state. A search for sequence motifs within this region crucial for PHF building revealed two Hexapeptides in the second and the third repeat. Some of the genetically linked cases of FTDP-17 show missense mutations in or adjacent to these Hexapeptide motifs. Proteins containing the P301L and the ΔK280 mutations exhibit accelerated aggregation. The importance of the two Hexapeptides stems from their capacity to undergo a conformational change from a random coil to a beta sheet structure. The increase of beta sheet structure is a typical feature of an amyloidogenic protein and is the basis of other characteristics like a decreased sensitivity towards proteolytic degradation and Congo red binding. PHFs aggregated in vitro and in vivo contain β-sheet structure, as judged by circular dichroism (CD) spectroscopy, Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction.
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mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta structure
Journal of Biological Chemistry, 2001Co-Authors: Martin Von Bergen, Stefan Barghorn, Jacek Biernat, Eva-maria Mandelkow, Alexander MarxAbstract:Abstract The microtubule-associated protein tau is a natively unfolded protein in solution, yet it is able to polymerize into the ordered paired helical filaments (PHF) of Alzheimer's disease. In the splice isoforms lacking exon 10, this process is facilitated by the formation of β-structure around the Hexapeptide motif PHF6 (306VQIVYK311) encoded by exon 11. We have investigated the structural requirements for PHF polymerization in the context of adult tau isoforms containing four repeats (including exon 10). In addition to the PHF6 motif there exists a related PHF6* motif (275VQIINK280) in the repeat encoded by the alternatively spliced exon 10. We show that this PHF6* motif also promotes aggregation by the formation of β-structure and that there is a cross-talk between the two Hexapeptide motifs during PHF aggregation. We also show that two of the tau mutations found in hereditary frontotemporal dementias, ΔK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for β-structure around the Hexapeptide motifs.
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mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta structure
Journal of Biological Chemistry, 2001Co-Authors: Martin Von Bergen, Stefan Barghorn, Jacek Biernat, Eva-maria Mandelkow, Alexander MarxAbstract:The microtubule-associated protein tau is a natively unfolded protein in solution, yet it is able to polymerize into the ordered paired helical filaments (PHF) of Alzheimer's disease. In the splice isoforms lacking exon 10, this process is facilitated by the formation of beta-structure around the Hexapeptide motif PHF6 ((306)VQIVYK(311)) encoded by exon 11. We have investigated the structural requirements for PHF polymerization in the context of adult tau isoforms containing four repeats (including exon 10). In addition to the PHF6 motif there exists a related PHF6* motif ((275)VQIINK(280)) in the repeat encoded by the alternatively spliced exon 10. We show that this PHF6* motif also promotes aggregation by the formation of beta-structure and that there is a cross-talk between the two Hexapeptide motifs during PHF aggregation. We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the Hexapeptide motifs.