# Phosphorylation disrupts the interaction between the intrinsically disordered region of the oncogenic NDRG1 and lipid vesicles

## TL;DR

This study explores how phosphorylation affects the NDRG1 protein's interaction with lipid vesicles, potentially offering new insights for treating nickel-related lung cancer.

## Contribution

The study provides a mechanistic understanding of how phosphorylation modulates NDRG1's function as a molecular switch in cancer-related processes.

## Key findings

- Phosphorylation modulates NDRG1's subcellular localization and lipid trafficking.
- NDRG1 toggles between membrane-bound and soluble states via phosphorylation.
- The findings suggest potential therapeutic targets for nickel-driven lung cancer.

## Abstract

NDRG1 is a multifunctional regulatory human protein implicated in crucial cellular processes and acting as a central hub of a cancer‐related interactome. In lung cancer, increased NDRG1 expression is associated with resistance to chemotherapy and is linked to the cellular response to nickel, a known tumor driver in air pollution. Although NDRG1 has been extensively studied in relation to cancer and lipid vesicle recycling, its precise molecular mechanisms remain poorly defined. To address this gap, the present work shifts the focus from previous cellular‐level investigations into a molecular‐level study of NDRG1, dissecting the effects of phosphorylation, metal binding, and lipid interactions. Specifically, we investigated the C‐terminal intrinsically disordered region of the protein that is a key regulatory hub and an attractive target for drug development. Employing a multimodal approach, which combines circular dichroism (CD), nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), Fourier‐transform infrared spectroscopy (FT‐IR), and isothermal titration calorimetry (ITC), we developed a mechanistic rationale for how phosphorylation modulates protein subcellular localization, lipid trafficking and storage, acting as a molecular switch that toggles NDRG1 between membrane‐bound, adhesion‐supporting states and soluble, signaling‐competent conformations with metal‐binding activity. These insights open potential opportunities for therapeutic intervention in nickel and pollution‐driven lung cancer.