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A novel protein synthesis method

The chemical synthesis of proteins is a rather cumbersome process and cannot fully recapitulate the native structure. An improvement to an existing method may provide the answer to protein synthesis.
A novel protein synthesis method
Proteins are key molecules in most biochemical and communication processes. Their function is largely determined by their three-dimensional configuration, and by the modifications they undergo following translation. Incorrect protein folding leads to aggregation and formation of amyloids, a hallmark of various neurodegenerative disorders.

Amyloidogenic diseases like familial amyloid polyneuropathy (FAP) are characterised by the aggregation of the protein transthyretin (TTR), which serves as a carrier of thyroxine and retinol. Structural analysis of misfolded TTR has indicated a deficiency in cysteine residues and disulphide bonds that eventually translates into improper configuration.

The scope of the EU-funded CYCLATTR (Application of novel cyclic ligation auxiliaries in the study of Transthyretin and derived pathologies) project was to develop a method for synthesising misfolded proteins for further studying their structure and function. In this context, they exploited the method of native chemical ligation (NCL), which has the unique capacity to add the native protein post-translational modifications.

The CYCLATTR method focused on overcoming drawbacks associated with previous tedious synthetic routes, slow ligation kinetics and harsh acidic removal. The milder conditions ensured the maintenance of sensitive post-translational modifications. The use of a special auxiliary led to a dramatic reduction in the duration of peptide bond formation between different amino acids.

Overall, the improved NCL method should help realise new applications in the chemical synthesis of recombinant proteins. A prime example is the synthesis of misfolded proteins like TTR that was previously not possible. Studying misfolded proteins is pivotal to understanding the mechanism behind their malfunction and could shed light on related neurodegenerative and other disorders.

Related information


Protein, chemical synthesis, transthyretin, native chemical ligation, post-translational modifications
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