AI-Redesigned Proteins Yield 79-Fold More Specific Ataxin-2 Protease
Updated
Updated · Nature.com · Jul 22
AI-Redesigned Proteins Yield 79-Fold More Specific Ataxin-2 Protease
2 articles · Updated · Nature.com · Jul 22
Summary
ProteinMPNN-redesigned botulinum proteases gave directed-evolution campaigns a stronger starting point, producing enzymes with higher stability, activity and specificity than wild-type proteins.
Across four side-by-side evolution campaigns, redesigned starters consistently reached higher-function variants and unlocked mutation paths that failed in wild-type backgrounds, showing greater mutational robustness and faster adaptation when nearby sequence fitness was raised.
For the disease-relevant target ataxin-2, proteases evolved from the redesigned BoNT/E background achieved more than 79-fold greater selected specificity than the best wild-type-derived variant while minimizing or eliminating detectable cleavage of the native SNAP25 substrate.
The study also showed redesign can restore performance to previously evolved enzymes: grafting 16 PTEN-targeting mutations into redesigned backgrounds improved expression up to 5.2-fold in bacteria and more than 24-fold in human cells while preserving reprogrammed specificity.
The authors present the workflow as a general route to engineer therapeutic or research enzymes, though they note broader applicability beyond these proteases still needs testing.
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AI-Guided Enzyme Engineering Achieves >17,000-Fold Reduction in Off-Target Cleavage: A Breakthrough for Disease-Specific Therapeutics
Overview
A major breakthrough in enzyme engineering was achieved by combining AI-guided sequence redesign with traditional laboratory evolution. Researchers used the AI tool ProteinMPNN to redesign and reprogram proteases, creating superior starting points for further evolution. This innovative approach overcame previous limitations of each method alone, setting a new standard in protein engineering. As a result, scientists reached unprecedented precision and control over enzyme activity, including a remarkable reduction in off-target effects. This advancement opens new possibilities for developing highly specific and safer enzyme-based therapies for complex diseases.