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Harnessing the Dark Side of Protein Folding: Manipulating Aggregation for Recombinant Protein Production

Objective

Nearly all desirable biological activities, whether for the purposes of nutrition, pharmacology, biofuel production, or waste disposal, can be carried out by proteins. Nature has furnished a vast array of bioactive and biocatalytic tools, and with the advent of rational protein design nearly any imaginable bioactivity is at our fingertips. There is, therefore, a pressing need for cost-effective, safe, and easily scalable strategies for generating Recombinant Proteins (rProteins). The main bottleneck for mass-producing a whole host of valuable biologically active rProteins is the difficulty of recovering functional proteins from expression hosts.

This difficulty stems largely from the lack of sufficient know-how for manipulating protein biogenesis in the cell. The key component of protein biology, whether in the context of rProtein production or cell viability, is enabling a protein to achieve its proper folding state. Most proteins do not fold on their own – they require the assistance of a vast network of folding managers, or chaperones. The cellular chaperone machinery not only assists protein folding, it also carries out quality control, ensuring that proteins that are damaged or unable to fold for other reasons are properly disposed of through degradation or protective aggregation.
The aim of this proposal is to understand the protein biosynthetic pathway in sufficient detail, so as to be able to manipulate its overall function. My eventual goal is to exert control over folding and aggregation in order to produce higher yields of functional rProteins in eukaryotes. The biotechnological strategy will consist of: 1. Manipulating aggregation to remove damaged endogenous proteins from the folding proteome, thus diverting more resources to the folding of rProteins; 2. Manipulating the allocation of cellular chaperone resources between folding, degradation, and aggregation; 3. Utilizing aggregates to produce substantially higher amounts of functional rProteins.

Call for proposal

ERC-2013-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

UNIVERSITAETSMEDIZIN GOETTINGEN - GEORG-AUGUST-UNIVERSITAET GOETTINGEN - STIFTUNG OEFFENTLICHEN RECHTS
Address
Robert-koch-strasse 40
37075 Goettingen
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 437 316
Principal investigator
Daniel Kaganovich (Dr.)
Administrative Contact
Reiner Mansch (Dr.)

Beneficiaries (2)

UNIVERSITAETSMEDIZIN GOETTINGEN - GEORG-AUGUST-UNIVERSITAET GOETTINGEN - STIFTUNG OEFFENTLICHEN RECHTS
Germany
EU contribution
€ 437 316
Address
Robert-koch-strasse 40
37075 Goettingen
Activity type
Higher or Secondary Education Establishments
Principal investigator
Daniel Kaganovich (Dr.)
Administrative Contact
Reiner Mansch (Dr.)
THE HEBREW UNIVERSITY OF JERUSALEM

Participation ended

Israel
EU contribution
€ 1 202 083
Address
Edmond J Safra Campus Givat Ram
91904 Jerusalem
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Hani Ben-Yehuda (Ms.)