Artificial Protein Crosstalk with a Molecule that Exchanges Binding Partners

Author:

Suss Ohad1,Halfin Olga1,Porat Ziv2,Fridmann Sirkis Yael3,Motiei Leila1,Margulies David1ORCID

Affiliation:

1. Department of Chemical and Structural Biology Weizmann Institute of Science Rehovot 7610001 Israel

2. Flow Cytometry Unit Life Sciences Core Facilities Weizmann Institute of Science Rehovot 7610001 Israel

3. Protein Analysis Unit Life Sciences Core Facilities Weizmann Institute of Science Rehovot 7610001 Israel

Abstract

AbstractDrawing 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.

Funder

Minerva Foundation

Publisher

Wiley

Subject

General Medicine

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