Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens

Cell Systems
Joshua PanCigall Kadoch

Abstract

Protein complexes are assemblies of subunits that have co-evolved to execute one or many coordinated functions in the cellular environment. Functional annotation of mammalian protein complexes is critical to understanding biological processes, as well as disease mechanisms. Here, we used genetic co-essentiality derived from genome-scale RNAi- and CRISPR-Cas9-based fitness screens performed across hundreds of human cancer cell lines to assign measures of functional similarity. From these measures, we systematically built and characterized functional similarity networks that recapitulate known structural and functional features of well-studied protein complexes and resolve novel functional modules within complexes lacking structural resolution, such as the mammalian SWI/SNF complex. Finally, by integrating functional networks with large protein-protein interaction networks, we discovered novel protein complexes involving recently evolved genes of unknown function. Taken together, these findings demonstrate the utility of genetic perturbation screens alone, and in combination with large-scale biophysical data, to enhance our understanding of mammalian protein complexes in normal and disease states.

Citations

Dec 24, 2018·Molecular Systems Biology·Evan A BoyleWilliam J Greenleaf
Jul 7, 2020·Molecular Systems Biology·Emanuel GonçalvesMathew J Garnett
Jan 3, 2019·Annual Review of Biochemistry·David K Breslow, Andrew J Holland
Feb 8, 2020·Nature Communications·Peter C DeWeirdtJohn G Doench
Jul 15, 2020·Nature Biotechnology·Peter C DeWeirdtJohn G Doench
Jul 19, 2019·Science Translational Medicine·Cigall Kadoch
Jan 4, 2019·Nature Cell Biology·Alfredo M Valencia, Cigall Kadoch
Apr 15, 2020·Nature Biotechnology·Ruth E Hanna, John G Doench
Apr 17, 2020·Nature·Katja LuckMichael A Calderwood
Oct 20, 2020·Molecular Systems Biology·Sumana SharmaEvangelia Petsalaki
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