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- Title
Artificial Protein Crosstalk with a Molecule that Exchanges Binding Partners.
- Authors
Suss, Ohad; Halfin, Olga; Porat, Ziv; Fridmann Sirkis, Yael; Motiei, Leila; Margulies, David
- Abstract
Drawing inspiration from allosteric signaling enzymes, whose catalytic and regulatory units are non‐covalently linked, we have devised a method to establish unnatural, effector‐mediated enzyme activation within native cells. The feasibility of this approach is demonstrated by introducing a synthetic regulatory unit (sRU) onto glycogen synthase kinase 3 (GSK‐3) through non‐covalent means. Our study reveals that this synthetic regulator mediates an unnatural crosstalk between GSK‐3 and lactate dehydrogenase A (LDHA), whose expression is regulated by cellular oxygen levels. Specifically, with this approach, the constitutively active GSK‐3 is transformed into an activable enzyme, whereas LDHA is repurposed as an unnatural effector protein that controls the activity of the kinase, making it unnaturally dependent on the cell's hypoxic response. These findings demonstrate a step toward imitating the function of effector‐regulated cell‐signaling enzymes, which play a key biological role in mediating the response of cells to changes in their environment. In addition, at the proof‐of‐principle level, our results indicate the potential to develop a new class of protein inhibitors whose inhibitory effect in cells is dictated by the cell's environment and consequent protein expression profile.
- Subjects
SYNTHETIC proteins; GLYCOGEN synthase kinase; ALLOSTERIC enzymes; ENZYME activation; MOLECULES
- Publication
Angewandte Chemie, 2024, Vol 136, Issue 7, p1
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.202312461