Signal for ER-associated degradation
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《细胞学杂志》
A major pathway for misfolded proteins is the ER-associated degradation (ERAD) pathway. On page 73, Spear and Ng show that misfolding is not enough to target a protein to ERAD. Rather, particular sugar residues act as signals.
The team used a shortened CPY protein as a model unfolded protein. CPY1 lacked the terminal 154 amino acids of the protein. Surprisingly, it was retained in the ER, rather than being targeted for ERAD. Although CPY contains four N-glycosylation sites, the team found that if they disrupted the last site—the one missing in CPY1—the protein was retained in the ER.To further test whether a single glycan could act as a signal for degradation, the team created two novel mutations in the ERAD substrate proteinase A*. When they mutated the first of two N-glycosylation sites in the protein, it was retained in the ER, like CPY1; but mutating the second site had no effect.
The team has started to further narrow down the features of the glycosylation sites that act as ERAD-entry signals. They have preliminary evidence that it is a bipartite signal, with a polypeptide sequence acting in conjunction with the sugar. If they move both together they can transfer the ERAD-targeting signal, independent of the rest of the protein. Remarkably, the glycosylation sites identified by Spear and Ng do not appear to have a function in the correctly folded protein, suggesting that they evolved for the purpose of targeting the protein for degradation when it misfolds.(CPY1 is a poor substrate for ERAD becaus)
The team used a shortened CPY protein as a model unfolded protein. CPY1 lacked the terminal 154 amino acids of the protein. Surprisingly, it was retained in the ER, rather than being targeted for ERAD. Although CPY contains four N-glycosylation sites, the team found that if they disrupted the last site—the one missing in CPY1—the protein was retained in the ER.To further test whether a single glycan could act as a signal for degradation, the team created two novel mutations in the ERAD substrate proteinase A*. When they mutated the first of two N-glycosylation sites in the protein, it was retained in the ER, like CPY1; but mutating the second site had no effect.
The team has started to further narrow down the features of the glycosylation sites that act as ERAD-entry signals. They have preliminary evidence that it is a bipartite signal, with a polypeptide sequence acting in conjunction with the sugar. If they move both together they can transfer the ERAD-targeting signal, independent of the rest of the protein. Remarkably, the glycosylation sites identified by Spear and Ng do not appear to have a function in the correctly folded protein, suggesting that they evolved for the purpose of targeting the protein for degradation when it misfolds.(CPY1 is a poor substrate for ERAD becaus)