Related Experiment Video

Updated: Sep 24, 2025

Genome-wide Protein-protein Interaction Screening by Protein-fragment Complementation Assay PCA in Living Cells
08:38

Genome-wide Protein-protein Interaction Screening by Protein-fragment Complementation Assay PCA in Living Cells

Published on: March 3, 2015

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Systematic discovery of mutation-directed neo-protein-protein interactions in cancer

Xiulei Mo1, Qiankun Niu2, Andrey A Ivanov3

  • 1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.

Cell
|May 5, 2022
PubMed

Insights

Cancer mutations can create new protein interactions, driving tumor growth. Our study identifies these novel interactions, revealing potential new therapeutic targets for precision medicine.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Genomic sequencing reveals cancer-driving mutations.
  • Some mutations cause neomorphic activity, altering protein function.
  • Neomorphic activity can lead to novel protein-protein interactions (neoPPIs).

Purpose of the Study:

  • To identify prevalent variant-enabled neoPPIs using a high-throughput screening platform.
  • To understand how cancer mutations create new protein interactions.
  • To explore therapeutic strategies based on these neoPPIs.

Main Methods:

  • Developed a quantitative high-throughput differential screening (qHT-dS) platform.
  • Coupled sensitive BRET biosensors with miniaturized coexpression in ultra-high-throughput screening (uHTS).
  • Monitored interactions of wild-type and mutant proteins with cancer-associated proteins in live cells.

Main Results:

  • Screened 17,792 interactions, generating over 2 million data points.
  • Identified a landscape of gain-of-interaction events linked to oncogenic and tumor suppressor mutations.
  • Discovered BRAF V600E mutation mediates KEAP1 neoPPI, creating a vulnerability to NQO1 substrates.

Conclusions:

  • Cancer genomic alterations can generate neo-interactions.
  • These neoPPIs offer insights into variant-directed therapeutic approaches.
  • Combination therapy targeting BRAF V600E/KEAP1 axis presents a potential strategy.
Keywords:
BRET(n)cancer genomicscancer targetdriver mutationsinteractomeneoPPIoncogeneprotein-protein interactionsystems biologytumor suppressor

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