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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.
Highlights
The general principle of quality control is of critical importance to the maintenance, function, and growth of biological cells
Newly-synthesized proteins are tagged by the attachment of a ‘glycan’ sugar chain which facilitates their binding to a chaperone that assists protein folding
Removal of a specific sugar group on the glycan ends the interaction with the chaperone, and not-yet-folded proteins can be re-tagged for another round of chaperone binding
Summary
The general principle of quality control is of critical importance to the maintenance, function, and growth of biological cells. Quality control is important for proteins, with a high fraction of proteome mass across the kingdoms of life devoted to protein homeostasis and folding [6]. Protein quality control begins with transcriptional proofreading by RNA polymerase [11] and continues with proofreading of tRNA matching to mRNA codons during translation [12] to reduce errors in the polypeptide sequence. We focus on post-translational quality control pathways that ensure nascent polypeptides fold into the correct or ‘native’ three-dimensional conformation, rather than roaming the cell in a misfolded state [13,14,15]
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