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Local and long-range stability in tandemly arrayed tetratricopeptide repeats

journal contribution
posted on 2023-06-07, 22:08 authored by Ewan R G Main, Katherine Stott, Sophie E Jackson, Lynne Regan
The tetratricopeptide repeat (TPR) is a 34-aa alpha-helical motif that occurs in tandem arrays in a variety of different proteins. In natural proteins, the number of TPR motifs ranges from 3 to 16 or more. These arrays function as molecular scaffolds and frequently mediate protein-protein interactions. We have shown that correctly folded TPR domain proteins, exhibiting the typical helix-turn-helix fold, can be designed by arraying tandem repeats of an idealized TPR consensus motif. To date, three designed proteins, CTPR1, CTPR2, and CTPR3 (consensus TPR number of repeats) have been characterized. Their high-resolution crystal structures show that the designed proteins indeed adopt the typical TPR fold, which is specified by the correct positioning of key residues. Here, we present a study of the thermodynamic properties and folding kinetics of this set of designed proteins. Chemical denaturation, monitored by CD and fluorescence, was used to assess the folding and global stability of each protein. NMR-detected amide proton exchange was used to investigate the stability of each construct at a residue-specific level. The results of these studies reveal a stable core, which defines the intrinsic stability of an individual TPR motif. The results also show the relationship between the number of tandem repeats and the overall stability and folding of the protein


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  • Published


Proceedings of the National Academy of Sciences




National Academy of Sciences





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Department affiliated with

  • Chemistry Publications


ERGM was first author (designed, performed, analyzed and wrote the majority of the work). The paper describes one of the first biophysical studies on repeat proteins (how stability / folding changes on increasing protein size). The research has been presented at a number of international conferences.

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