Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks

TY - JOUR

T1 - Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks

AU - Chung, Sun Sook

AU - Ng, Joseph C.F.

AU - Laddach, Anna

AU - Thomas, N. Shaun B.

AU - Fraternali, Franca

N1 - Publisher Copyright: © 2021 The Author(s).

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Direct drug targeting of mutated proteins in cancer is not always possible and efficacy can be nullified by compensating protein-protein interactions (PPIs). Here, we establish an in silico pipeline to identify specific PPI sub-networks containing mutated proteins as potential targets, which we apply to mutation data of four different leukaemias. Our method is based on extracting cyclic interactions of a small number of proteins topologically and functionally linked in the Protein-Protein Interaction Network (PPIN), which we call short loop network motifs (SLM). We uncover a new property of PPINs named 'short loop commonality' to measure indirect PPIs occurring via common SLM interactions. This detects 'modules' of PPI networks enriched with annotated biological functions of proteins containing mutation hotspots, exemplified by FLT3 and other receptor tyrosine kinase proteins. We further identify functional dependency or mutual exclusivity of short loop commonality pairs in large-scale cellular CRISPR-Cas9 knockout screening data. Our pipeline provides a new strategy for identifying new therapeutic targets for drug discovery.

AB - Direct drug targeting of mutated proteins in cancer is not always possible and efficacy can be nullified by compensating protein-protein interactions (PPIs). Here, we establish an in silico pipeline to identify specific PPI sub-networks containing mutated proteins as potential targets, which we apply to mutation data of four different leukaemias. Our method is based on extracting cyclic interactions of a small number of proteins topologically and functionally linked in the Protein-Protein Interaction Network (PPIN), which we call short loop network motifs (SLM). We uncover a new property of PPINs named 'short loop commonality' to measure indirect PPIs occurring via common SLM interactions. This detects 'modules' of PPI networks enriched with annotated biological functions of proteins containing mutation hotspots, exemplified by FLT3 and other receptor tyrosine kinase proteins. We further identify functional dependency or mutual exclusivity of short loop commonality pairs in large-scale cellular CRISPR-Cas9 knockout screening data. Our pipeline provides a new strategy for identifying new therapeutic targets for drug discovery.

UR - http://www.scopus.com/inward/record.url?scp=85123224755&partnerID=8YFLogxK

U2 - 10.1093/nargab/lqab010

DO - 10.1093/nargab/lqab010

M3 - Article

AN - SCOPUS:85123224755

SN - 2631-9268

VL - 3

JO - NAR Genomics and Bioinformatics

JF - NAR Genomics and Bioinformatics

IS - 1

M1 - lqab010

ER -