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Cooperative stabilisation of 14-3-3σ protein–protein interactions via covalent protein modification

DOI: 10.1039/D1SC02120F DOI Help

Authors: Marta Falcicchio (University of Leicester) , Jake A. Ward (University of Leicester) , Sara Y. Chothia (University of Leicester) , Jaswir Basran (University of Leicester) , Alisha Mohindra (University of Leicester) , Salvador Macip (University of Leicester; Universitat Oberta de Catalunya) , Pietro Roversi (University of Leicester; IBBA-CNR Unit of Milano) , Richard G. Doveston (University of Leicester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 61

State: Published (Approved)
Published: September 2021

Open Access Open Access

Abstract: 14-3-3 proteins are an important family of hub proteins that play important roles in many cellular processes via a large network of interactions with partner proteins. Many of these protein–protein interactions (PPI) are implicated in human diseases such as cancer and neurodegeneration. The stabilisation of selected 14-3-3 PPIs using drug-like ‘molecular glues’ is a novel therapeutic strategy with high potential. However, the examples reported to date have a number of drawbacks in terms of selectivity and potency. Here, we report that WR-1065, the active species of the approved drug amifostine, covalently modifies 14-3-3σ at an isoform-unique cysteine residue, Cys38. This modification leads to isoform-specific stabilisation of two 14-3-3σ PPIs in a manner that is cooperative with a well characterised molecular glue, fusicoccin A. Our findings reveal a novel stabilisation mechanism for 14-3-3σ, an isoform with particular involvement in cancer pathways. This mechanism can be exploited to harness the enhanced potency conveyed by covalent drug molecules and dual ligand cooperativity. This is demonstrated in two cancer cell lines whereby the cooperative behaviour of fusicoccin A and WR-1065 leads to enhanced efficacy for inducing cell death and attenuating cell growth.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 27/09/2021 14:39


Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)