Protein folding and secretion: mechanistic insights advancing recombinant protein production in S. cerevisiae

Abstract

The emergence of genomic approaches coupled to recombinant DNA technologies have identified the quality control systems that regulate proteostasis - biological pathways that modulate protein biogenesis, maturation, trafficking, and degradation. The elucidation of these pathways has become of growing importance in therapeutics as loss of proteostasis has been suggested to lead to a number of human diseases including Alzheimer's, Parkinson's Disease and Type II Diabetes. We anticipate that the most successful strategies for protein expression and therapeutics development may involve integration of protein engineering strategies with host manipulation, to exploit the cell's native stress response pathways and trafficking mechanisms. This review will highlight recent findings and mechanistic detail correlated to quality control in the early secretory pathway of Saccharomyces cerevisiae.

Figure 1. ER Quality Control Mechanisms

Selected chaperone interactions facilitate ER protein translocation, folding and maturation, and ERAD. Post-translation modifications including disulfide bond formation and glycosylation are also illustrated.

Figure 2. Quality Control in the Secretory Pathway

In addition to ER-to-Golgi secretion, alternate routes of protein trafficking have been established in S. cerevisiae. To alleviate ER stress, organelle morphology may be significantly altered by mechanisms such as ER-phagy or the formation of ER-mitochondria encounter structures (ERMES).