Proteostasis Engineering

Protein homeostasis networks and their biotechnological application  

In all cell types, protein homeostasis or “proteostasis” is maintained by sophisticated quality control (QC) networks that regulate protein synthesis, folding, trafficking, aggregation, disaggregation, and degradation. Our early work revealed the existence of a QC mechanism along the twin-arginine translocation pathway for discriminating folded proteins from those that are misfolded and/or aggregated (PNAS 2003; PNAS 2012). We have subsequently leveraged this folding QC mechanism for the creation of numerous biotechnological applications (Nat Commun 2019; PNAS 2009). Beyond the Tat system, we have also exploited cellular proteostasis mechanisms in a number of other ways including the creation of technologies for rendering membrane proteins water-soluble (Nat Commun 2015; Nat Chem Biol 2017) and for targeted protein degradation (ACS Cent Sci 2019; J Biol Chem 2014).

Notable contributions include: 

(i) the first reported biosynthesis of full-length antibodies in the cytoplasm of bacteria (Nat Commun 2015)


(ii) one of the first examples of ordered arrangement (“scaffolding”) of metabolic enzymes for improved pathway performance (Nucleic Acid Res 2012; Metab Eng 2007)


(iii) a novel approach for engineering water-soluble variants of integral membrane proteins (Nat Commun 2015) that were subsequently used to build an unnatural pathway for disulfide bond formation in the cytoplasm of bacteria (Nat Chem Biol 2017)


(iv) creation of a generalizable protein knockout method by engineering protein chimeras called “ubiquibodies” that combine the activity of E3 ubiquitin ligases with designer binding proteins to steer virtually any protein to the proteasome for degradation (J Biol Chem 2014; ACS Cent Sci 2019)

Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University

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