AI Article Synopsis
- The study explores how the function of proteins shapes their fitness landscapes, distinguishing between smooth landscapes (where small changes lead to gradual function variations) and rugged landscapes (where changes result in unpredictable function shifts).
- Through examining 1,158 sequences from the LacI/GalR transcriptional repressor family, the research found a rugged landscape with rapid changes in specificity between closely related sequences.
- The ruggedness of this landscape is linked to the need for the repressor to evolve a specific function while avoiding conflicting regulatory interactions, providing new insights into the evolution of genetic regulation.
Article Abstract
How a protein's function influences the shape of its fitness landscape, smooth or rugged, is a fundamental question in evolutionary biochemistry. Smooth landscapes arise when incremental mutational steps lead to a progressive change in function, as commonly seen in enzymes and binding proteins. On the other hand, rugged landscapes are poorly understood because of the inherent unpredictability of how sequence changes affect function. Here, we experimentally characterize the entire sequence phylogeny, comprising 1,158 extant and ancestral sequences, of the DNA-binding domain (DBD) of the LacI/GalR transcriptional repressor family. Our analysis revealed an extremely rugged landscape with rapid switching of specificity, even between adjacent nodes. Further, the ruggedness arises due to the necessity of the repressor to simultaneously evolve specificity for asymmetric operators and disfavors potentially adverse regulatory crosstalk. Our study provides fundamental insight into evolutionary, molecular, and biophysical rules of genetic regulation through the lens of fitness landscapes.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299162 | PMC |
| http://dx.doi.org/10.1016/j.cels.2024.03.002 | DOI Listing |
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