ArticleProceedings of the National Academy of Sciences of the United States of America2012
Control of protein signaling using a computationally designed GTPase/GEF orthogonal pair.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed.
- Engineered interfaces in Rac1 and Cdc42 biosensors enhance sensitivity and reduce cell perturbation.Molecular biology of the cell · 2026Article
- Noise-Guided Design of Synthetic Protein Waves in Living Cells.ACS synthetic biology · 2026Article
- Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators.Communications chemistry · 2024Article
- Exploring the Structural and Dynamic Properties of a Chimeric Glycoside Hydrolase Protein in the Presence of Calcium Ions.International journal of molecular sciences · 2024Article
- Review
- Programmable protein circuit design.Cell · 2021Review
- Structural basis for selective AMPylation of Rac-subfamily GTPases byProceedings of the National Academy of Sciences of the United States of America · 2021Article
- GαThe Journal of biological chemistry · 2020Article
- Macromolecular modeling and design in Rosetta: recent methods and frameworks.Nature methods · 2020Review
- SAXS studies of X-ray induced disulfide bond damage: Engineering high-resolution insight from a low-resolution technique.PloS one · 2020Article
- Comparison of Rosetta flexible-backbone computational protein design methods on binding interactions.Proteins · 2020Article
- Advances in protein structure prediction and design.Nature reviews. Molecular cell biology · 2019Review
- Computational design of structured loops for new protein functions.Biological chemistry · 2019Review
- Ultrahigh specificity in a network of computationally designed protein-interaction pairs.Nature communications · 2018Article
- Computational design of chemogenetic and optogenetic split proteins.Nature communications · 2018Article
- Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Flex ddG: Rosetta Ensemble-Based Estimation of Changes in Protein-Protein Binding Affinity upon Mutation.The journal of physical chemistry. B · 2018Article
- Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes.Science (New York, N.Y.) · 2018Article
- Reprogramming cellular functions with engineered membrane proteins.Current opinion in biotechnology · 2017Review
- Mammalian synthetic biology for studying the cell.The Journal of cell biology · 2017Review
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Authors and funding
10 authors.
Funding
Abstract
Signaling pathways depend on regulatory protein-protein interactions; controlling these interactions in cells has important applications for reengineering biological functions. As many regulatory proteins are modular, considerable progress in engineering signaling circuits has been made by recombining commonly occurring domains. Our ability to predictably engineer cellular functions, however, is constrained by complex crosstalk observed in naturally occurring domains. Here we demonstrate a strategy for improving and simplifying protein network engineering: using computational design to create orthogonal (non-crossreacting) protein-protein interfaces. We validated the design of the interface between a key signaling protein, the GTPase Cdc42, and its activator, Intersectin, biochemically and by solving the crystal structure of the engineered complex. The designed GTPase (orthoCdc42) is activated exclusively by its engineered cognate partner (orthoIntersectin), but maintains the ability to interface with other GTPase signaling circuit components in vitro. In mammalian cells, orthoCdc42 activity can be regulated by orthoIntersectin, but not wild-type Intersectin, showing that the designed interaction can trigger complex processes. Computational design of protein interfaces thus promises to provide specific components that facilitate the predictable engineering of cellular functions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.