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An adaptable standard for protein export from the endoplasmic reticulum
R Luke Wiseman1, Evan T Powers, Joel N Buxbaum
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell
|November 21, 2007
Summary
Cellular protein export from the endoplasmic reticulum (ER) depends on a complex network balancing folding energetics and pathway capacities. This network view offers insights into protein homeostasis and disease, guiding strategies for therapeutic intervention.
Area of Science:
- Cellular Biology
- Biophysics
- Systems Biology
Background:
- Endoplasmic reticulum (ER) protein folding and export are crucial for cellular function.
- Protein homeostasis (proteostasis) involves complex networks of folding, degradation, and transport pathways.
- Dysregulation of these pathways is linked to various diseases.
Purpose of the Study:
- To integrate the understanding of ER protein export by examining the interplay between folding energetics and cellular pathway adaptability.
- To develop a framework for interpreting protein folding kinetics and thermodynamics within the context of cellular protein trafficking.
- To identify key factors and network dynamics that govern protein export efficiency from the ER.
Main Methods:
- Development of a simplified model for the protein homeostasis network.
- Formalism to interpret protein folding kinetics and thermodynamics within competing pathways.
- Modeling of folding for export (FoldEx) to analyze efficiency determinants.
Main Results:
- Protein export efficiency is not dictated by a single factor but by the network's collective dynamics.
- Folding and misfolding energetics, alongside adjustable pathway capacities, determine the standard for ER protein export.
- The network view explains cellular diversity and disease origins related to protein misfolding.
Conclusions:
- A network-centric approach is essential for understanding protein homeostasis and cellular trafficking.
- The FoldEx model provides a framework for predicting strategies to restore proteostasis in disease.
- Interventions targeting the entire network, rather than single components, may be most effective for treating protein-misfolding diseases.
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