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A common mechanism for posttranslational activation of plasma membrane receptors?
1Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Abstract:
The process for posttranslational acquisition of ligand binding function is remarkably similar for three receptors with dissimilar structures, namely, the insulin, epidermal growth factor, and acetylcholine receptors. These receptors lack the ability to bind ligand immediately after translation, but slowly (t1/2 = 30-45 min) acquire this capacity while in the endoplasmic reticulum. This activation step occurs with similar kinetics for all three receptors and, in each case, required N-linked glycosylation. Several lines of evidence suggest a common mechanism for the acquisition of ligand binding function that involves the rearrangement of metastable disulfide bonds formed during or immediately after translation. This process precedes subunit assembly of both insulin and acetylcholine receptors, which also occurs in the endoplasmic reticulum. The posttranslational processing steps leading to the acquisition of ligand binding function may be an example of a more general process affecting cell surface proteins.
Insights
Receptor activation, including for insulin and acetylcholine receptors, involves a slow posttranslational process in the endoplasmic reticulum. This common mechanism requires N-linked glycosylation and disulfide bond rearrangement for ligand binding acquisition.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Receptors like insulin, EGF, and acetylcholine are crucial for cell signaling.
- These receptors initially lack ligand-binding capacity after translation.
Purpose of the Study:
- To investigate the common mechanism of posttranslational acquisition of ligand binding function across different receptor types.
- To elucidate the role of N-linked glycosylation and disulfide bond rearrangement in receptor activation.
Main Methods:
- Comparative analysis of posttranslational processing in insulin, EGF, and acetylcholine receptors.
- Kinetic studies of ligand binding acquisition.
- Investigation of N-linked glycosylation and disulfide bond formation/rearrangement.
Main Results:
- All three receptors acquire ligand binding function slowly (t1/2 = 30-45 min) in the endoplasmic reticulum.
- This activation process requires N-linked glycosylation and involves rearrangement of disulfide bonds.
- Disulfide bond rearrangement precedes subunit assembly for insulin and acetylcholine receptors.
Conclusions:
- A common mechanism involving posttranslational disulfide bond rearrangement and N-linked glycosylation facilitates ligand binding in diverse receptors.
- This process is essential for receptor function and may apply to other cell surface proteins.