ArticleProceedings of the National Academy of Sciences of the United States of America2010
Engineering an artificial zymogen by alternate frame protein folding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 37 citations in OpenAlex.
- Enhancing response of a protein conformational switch by using two disordered ligand binding domains.Frontiers in molecular biosciences · 2023Article
- Bioluminescence Goes Dark: Boosting the Performance of Bioluminescent Sensor Proteins Using Complementation Inhibitors.ACS sensors · 2022Article
- Engineering protein activity into off-the-shelf DNA devices.Cell reports methods · 2022Article
- Massively parallel, computationally guided design of a proenzyme.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Engineering and exploiting synthetic allostery of NanoLuc luciferase.Nature communications · 2022Article
- Influence of Secondary-Structure Folding on the Mutually Exclusive Folding Process of GL5/I27 Protein: Evidence from Molecular Dynamics Simulations.International journal of molecular sciences · 2016Article
- Protease-based synthetic sensing and signal amplification.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Design of catalytically amplified sensors for small molecules.Biomolecules · 2014Review
- GFP variants with alternative β-strands and their application as light-driven protease sensors: a tale of two tails.Journal of the American Chemical Society · 2013Article
- Regulated unfolding of proteins in signaling.FEBS letters · 2013Review
- Stepwise conversion of a binding protein to a fluorescent switch: application to Thermoanaerobacter tengcongensis ribose binding protein.Biochemistry · 2013Article
- Protein conformational switches: from nature to design.Chemistry (Weinheim an der Bergstrasse, Germany) · 2012Review
- Structural characterization of two alternate conformations in a calbindin D₉k-based molecular switch.Biochemistry · 2011Article
- Molecular simulations of mutually exclusive folding in a two-domain protein switch.Biophysical journal · 2011Article
- Converting a protein into a switch for biosensing and functional regulation.Protein science : a publication of the Protein Society · 2011Review
- Article
- Protease activation of split green fluorescent protein.Chembiochem : a European journal of chemical biology · 2010Article
- A switch-on mechanism to activate maize ribosome-inactivating protein for targeting HIV-infected cells.Nucleic acids research · 2010Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Alternate frame folding (AFF) is a novel mechanism by which allostery can be introduced into a protein where none may have existed previously. We employ this technology to convert the cytotoxic ribonuclease barnase into an artificial zymogen that is activated by HIV-1 protease. The AFF modification entails partial duplication of the polypeptide chain and mutation of a key catalytic residue in one of the duplicated segments. The resulting molecule can fold in one of two "frames" to yield the wild-type structure or a circularly permuted form in which the positions of the N- and C-termini are exchanged with a surface loop. It cannot take on both structures simultaneously because each competes for a shared amino acid sequence. An HIV-1 protease recognition sequence is inserted into one of the surface loops in the nonpermuted frame, and cleavage induces a shift from the nonpermuted fold to the permuted fold. Using the AFF mechanism, we were able to suppress k(cat)/K(M) by 250-fold in the proenzyme relative to wild-type barnase. HIV-1 protease cleavage subsequently increases k(cat)/K(M) by 130-fold. AFF is significant because it is general and can in principle be used to control activity of many enzymes, including those whose functions are not regulated by any existing mechanism.
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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.