a(MESH:Ubiquitin)
Following degradation of the substrate, short peptides are released along with free and reusable ubiquitin. PubMed:14556719
Initially, the ubiquitin-activating enzyme E1 activates ubiquitin in an ATP-requiring reaction to generate a high-energy thiol ester intermediate, E1-S~ubiquitin, where ubiquitin is bound to an internal E1 Cys residue PubMed:14556719
An E1 enzyme must first activate ubiquitin, a highly conserved, 76 amino acid polypeptide, in an ATP-dependent manner. PubMed:24457024
E1s are multidomain enzymes that must activate ubiquitin and efficiently transfer it to the E2 active site PubMed:24457024
We soon found that DF2 strongly stained cortical and brain stem Lewy bodies in brain sections from “diffuse Lewy body disease” (Kuzuhara et al. 1988), as originally described by Kenji Kosaka (1978), who proposed that some elderly subjects dying with dementia had many cortical Lewy bodies PubMed:22908190
The DF2 immunoreactivity of Lewy bodies led us to search for similar DF2-positive inclusions, and we found that Lewy-like bodies in motor neurons in amyotrophic lateral sclerosis (ALS; Murayama et al. 1990a) and Pick bodies in Pick’s disease (Murayama et al. 1990b) were strongly reactive; the latter stained also for tau, whereas the former stained neither for tau nor a-synuclein. PubMed:22908190
The DF2 immunoreactivity of Lewy bodies led us to search for similar DF2-positive inclusions, and we found that Lewy-like bodies in motor neurons in amyotrophic lateral sclerosis (ALS; Murayama et al. 1990a) and Pick bodies in Pick’s disease (Murayama et al. 1990b) were strongly reactive; the latter stained also for tau, whereas the former stained neither for tau nor a-synuclein. PubMed:22908190
In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected. PubMed:22908190
In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected. PubMed:22908190
Besides the characteristic “PHF smear,” they also labeled a very small protein of ~8 kDa. Hiroshi Mori named these monoclonal antibodies DF (Dementia Filament) 1 and 2, of which the latter (DF2) was used for subsequent characterization (Mori et al. 1987). PubMed:22908190
In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected. PubMed:22908190
The first step is activation of the carboxyl terminus of Ub by an E1 protein (i.e., a Ub-activating enzyme), which consumes ATP. PubMed:22908190
In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected. PubMed:22908190
In addition, DF2 intensely labeled the classical granulovacuolar changes in the hippocampus in AD and other neurodegenerative disorders (Fig. 1, inset). PubMed:22908190
For instance, ubiquitin can recruit other factors to mediate various cellular responses such as signaling, gene regulation, endocytosis, macro-autophagy, and DNA repair PubMed:24457024
For instance, ubiquitin can recruit other factors to mediate various cellular responses such as signaling, gene regulation, endocytosis, macro-autophagy, and DNA repair PubMed:24457024
Initially, the ubiquitin-activating enzyme E1 activates ubiquitin in an ATP-requiring reaction to generate a high-energy thiol ester intermediate, E1-S~ubiquitin, where ubiquitin is bound to an internal E1 Cys residue PubMed:14556719
For instance, ubiquitin can recruit other factors to mediate various cellular responses such as signaling, gene regulation, endocytosis, macro-autophagy, and DNA repair PubMed:24457024
For instance, ubiquitin can recruit other factors to mediate various cellular responses such as signaling, gene regulation, endocytosis, macro-autophagy, and DNA repair PubMed:24457024
This function is crucial for cellular homeostasis because failure to activate ubiquitin, as seen by the chemical inhibition of E1 activity in the cell, results in the almost immediate shutdown of the entire UPS PubMed:24457024
Besides the characteristic “PHF smear,” they also labeled a very small protein of ~8 kDa. Hiroshi Mori named these monoclonal antibodies DF (Dementia Filament) 1 and 2, of which the latter (DF2) was used for subsequent characterization (Mori et al. 1987). PubMed:22908190
In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected. PubMed:22908190
In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected. PubMed:22908190
In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected. PubMed:22908190
In addition, DF2 intensely labeled the classical granulovacuolar changes in the hippocampus in AD and other neurodegenerative disorders (Fig. 1, inset). PubMed:22908190
In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected. PubMed:22908190
We soon found that DF2 strongly stained cortical and brain stem Lewy bodies in brain sections from “diffuse Lewy body disease” (Kuzuhara et al. 1988), as originally described by Kenji Kosaka (1978), who proposed that some elderly subjects dying with dementia had many cortical Lewy bodies PubMed:22908190
The DF2 immunoreactivity of Lewy bodies led us to search for similar DF2-positive inclusions, and we found that Lewy-like bodies in motor neurons in amyotrophic lateral sclerosis (ALS; Murayama et al. 1990a) and Pick bodies in Pick’s disease (Murayama et al. 1990b) were strongly reactive; the latter stained also for tau, whereas the former stained neither for tau nor a-synuclein. PubMed:22908190
The DF2 immunoreactivity of Lewy bodies led us to search for similar DF2-positive inclusions, and we found that Lewy-like bodies in motor neurons in amyotrophic lateral sclerosis (ALS; Murayama et al. 1990a) and Pick bodies in Pick’s disease (Murayama et al. 1990b) were strongly reactive; the latter stained also for tau, whereas the former stained neither for tau nor a-synuclein. PubMed:22908190
Second, there is conjugation of the ATP-activated Ub to an E2 protein (i.e., a Ub-conjugating enzyme). PubMed:22908190
Ubiquitin, the crucial signal for efficient sorting of proteins into the MVB (Babst et al. 1997), initiates this process, which is mediated by a group of ESCRT complexes (endosomal sorting complex required for transport; Hurley 2010). PubMed:22908190
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.