Bibliographic Details
| Title: |
De novo design of knotted tandem repeat proteins. |
| Authors: |
Doyle, Lindsey A., Takushi, Brittany, Kibler, Ryan D., Milles, Lukas F., Orozco, Carolina T., Jones, Jonathan D., Jackson, Sophie E., Stoddard, Barry L., Bradley, Philip |
| Source: |
Nature Communications; 10/24/2023, Vol. 14 Issue 1, p1-17, 17p |
| Subject Terms: |
X-ray crystallography, TANDEM repeats, KNOT theory, PROTEIN engineering, PROTEIN folding, PROTEIN structure |
| Abstract: |
De novo protein design methods can create proteins with folds not yet seen in nature. These methods largely focus on optimizing the compatibility between the designed sequence and the intended conformation, without explicit consideration of protein folding pathways. Deeply knotted proteins, whose topologies may introduce substantial barriers to folding, thus represent an interesting test case for protein design. Here we report our attempts to design proteins with trefoil (31) and pentafoil (51) knotted topologies. We extended previously described algorithms for tandem repeat protein design in order to construct deeply knotted backbones and matching designed repeat sequences (N = 3 repeats for the trefoil and N = 5 for the pentafoil). We confirmed the intended conformation for the trefoil design by X ray crystallography, and we report here on this protein's structure, stability, and folding behaviour. The pentafoil design misfolded into an asymmetric structure (despite a 5-fold symmetric sequence); two of the four repeat-repeat units matched the designed backbone while the other two diverged to form local contacts, leading to a trefoil rather than pentafoil knotted topology. Our results also provide insights into the folding of knotted proteins. This study reports the successful de novo design of a trefoil knotted protein fold for which the crystal structure agrees closely with the intended trefoil knot topology. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
