De novo selection of oncogenes

Proceedings of the National Academy of Sciences of the United States of America
Kelly M ChacónDaniel DiMaio

Abstract

All cellular proteins are derived from preexisting ones by natural selection. Because of the random nature of this process, many potentially useful protein structures never arose or were discarded during evolution. Here, we used a single round of genetic selection in mouse cells to isolate chemically simple, biologically active transmembrane proteins that do not contain any amino acid sequences from preexisting proteins. We screened a retroviral library expressing hundreds of thousands of proteins consisting of hydrophobic amino acids in random order to isolate four 29-aa proteins that induced focus formation in mouse and human fibroblasts and tumors in mice. These proteins share no amino acid sequences with known cellular or viral proteins, and the simplest of them contains only seven different amino acids. They transformed cells by forming a stable complex with the platelet-derived growth factor β receptor transmembrane domain and causing ligand-independent receptor activation. We term this approach de novo selection and suggest that it can be used to generate structures and activities not observed in nature, create prototypes for novel research reagents and therapeutics, and provide insight into cell biology, transmembrane p...Continue Reading

References

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Citations

Apr 20, 2014·Annual Review of Microbiology·Daniel DiMaio
Aug 12, 2015·Proceedings of the National Academy of Sciences of the United States of America·Erin N HeimDaniel DiMaio
May 12, 2019·Genome Biology and Evolution·Anouk WillemsenIgnacio G Bravo
Feb 9, 2020·Nature Communications·Nikolaos VakirlisAnne-Ruxandra Carvunis
Jul 14, 2019·Journal of Molecular Biology·Ross S FedermanDaniel DiMaio
Sep 3, 2021·Journal of Molecular Biology·Lisa M PettiDaniel DiMaio

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