Journal
SCIENCE
Volume 368, Issue 6486, Pages 78-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aay2790
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Funding
- Howard Hughes Medical Institute
- IPD-WA State [Y5/07-5568]
- NIH BTRR Yeast Resource Grant [Y8-12/61-3650]
- Bruce and Jeannie Nordstrom/Patty and Jimmy Barrier Gift for the Institute for Protein Design
- Spark [ABCA4/63-3819]
- NIH P41 grant [GM103533]
- Burroughs Wellcome Fund Career Award at the Scientific Interface
- Army Research Office [W911NF-18-1-0200]
- Air Force Research Laboratory Center of Excellence grant [FA8650-15-2-5518]
- David and Lucile Packard Foundation
- Camille Dreyfus Teacher-Scholar Program
- Department of Defense (DOD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program
- NHLBI [7R33HL120752]
- NIH [P41 GM128577, P30 GM124169-01, ALS-ENABLE P30 GM124169, S10OD018483]
- Ohio Eminent Scholar funds
- Defense Advanced Research Projects Agency [HR0011-16-20045]
- NCI SBDR [CA92584]
- DOE-BER IDAT [DE-AC0205CH11231]
- [EMBO/80-7223]
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The design of modular protein logic for regulating protein function at the posttranscriptional level is a challenge for synthetic biology. Here, we describe the design of two-input AND, OR, NAND, NOR, XNOR, and NOT gates built from de novo-designed proteins. These gates regulate the association of arbitrary protein units ranging from split enzymes to transcriptional machinery in vitro, in yeast and in primary human T cells, where they control the expression of the TIM3 gene related to T cell exhaustion. Designed binding interaction cooperativity, confirmed by native mass spectrometry, makes the gates largely insensitive to stoichiometric imbalances in the inputs, and the modularity of the approach enables ready extension to three-input OR, AND, and disjunctive normal form gates. The modularity and cooperativity of the control elements, coupled with the ability to de novo design an essentially unlimited number of protein components, should enable the design of sophisticated posttranslational control logic over a wide range of biological functions.
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