Design principles for the glycoprotein quality control pathway

TL;DR

This paper uses quantitative modeling to identify how energy-consuming cyclic processes optimize glycoprotein quality control in the ER, revealing key parameters for system efficiency and adaptability.

Contribution

It introduces a detailed quantitative model demonstrating that cyclic, energy-dependent pathways outperform alternative designs in glycoprotein quality control.

Findings

Cyclic quality-control processes outperform static ones.

Optimal parameters vary with protein production levels.

Adjusting degradation rates enhances pathway adaptability.

Abstract

Newly-translated glycoproteins in the endoplasmic reticulum (ER) often undergo cycles of chaperone binding and release in order to assist in folding. Quality control is required to distinguish between proteins that have completed native folding, those that have yet to fold, and those that have misfolded. Using quantitative modeling, we explore how the design of the quality-control pathway modulates its efficiency. Our results show that an energy-consuming cyclic quality-control process, similar to the observed physiological system, outperforms alternative designs. The kinetic parameters that optimize the performance of this system drastically change with protein production levels, while remaining relatively insensitive to the protein folding rate. Adjusting only the degradation rate, while fixing other parameters, allows the pathway to adapt across a range of protein production levels, aligning with in vivo measurements that implicate the release of degradation-associated enzymes as a rapid-response system for perturbations in protein homeostasis. The quantitative models developed here elucidate design principles for effective glycoprotein quality control in the ER, improving our mechanistic understanding of a system crucial to maintaining cellular health.