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08:59
4D Imaging of Protein Aggregation in Live Cells
Published on: April 5, 2013
Quality control for unfolded proteins at the plasma membrane
Pirjo M Apaja1, Haijin Xu, Gergely L Lukacs
1Department of Physiology, McGill University, Montréal, Quebec, Canada.
The Journal of Cell Biology
|October 27, 2010
Summary
Damaged plasma membrane proteins are degraded via a novel quality control pathway involving chaperones and ubiquitination, leading to lysosomal disposal. This mechanism impacts protein homeostasis and may contribute to conformational diseases.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cellular protein homeostasis relies on eliminating damaged proteins.
- Plasma membrane (PM) protein quality control is crucial for cell function.
- Conformationally impaired proteins pose a significant challenge to proteostasis.
Purpose of the Study:
- To investigate the molecular mechanisms of quality control for misfolded plasma membrane proteins.
- To elucidate the pathway for disposal of conformationally impaired PM proteins.
- To explore the role of chaperones and ubiquitination in this process.
Main Methods:
- Construction of CD4 chimeras with temperature-sensitive domains.
- Proteomic, biochemical, and genetic analyses.
- Bioluminescence resonance energy transfer and immunoblotting assays.
Main Results:
- Thermal unfolding of λ domain triggered chaperone (Hsp40/Hsc70/Hsp90) and E2-E3 complex recruitment.
- Mixed-chain polyubiquitination accelerated chimera internalization and lysosomal degradation.
- Impaired recycling and endosomal sorting complex required for transport (ESCRT)-dependent degradation were observed.
- Similar mechanisms were identified for mutant dopamine D4.4 and vasopressin V2 receptors.
Conclusions:
- A peripheral proteostatic mechanism disposes of conformationally impaired PM proteins.
- This pathway involves chaperones, ubiquitination, and ESCRT-mediated lysosomal targeting.
- Dysregulation of this mechanism may contribute to conformational diseases.
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