Genetic interaction mapping informs integrative structure determination of protein complexes

Hannes Braberg, Ignacia Echeverria, Stefan Bohn, Peter Cimermancic, Anthony Shiver, Richard Alexander, Jiewei Xu, Michael Shales, Raghuvar Dronamraju, Shuangying Jiang, Gajendradhar Dwivedi, Derek Bogdanoff, Kaitlin K. Chaung, Ruth Hüttenhain, Shuyi Wang, David Mavor, Riccardo Pellarin, Dina Schneidman, Joel S. Bader, James S. FraserJohn Morris, James E. Haber, Brian D. Strahl, Carol A. Gross, Junbiao Dai, Jef D. Boeke*, Andrej Sali*, Nevan J. Krogan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Determining structures of protein complexes is crucial for understanding cellular functions. Here, we describe an integrative structure determination approach that relies on in vivo measurements of genetic interactions. We construct phenotypic profiles for point mutations crossed against gene deletions or exposed to environmental perturbations, followed by converting similarities between two profiles into an upper bound on the distance between the mutated residues. We determine the structure of the yeast histone H3-H4 complex based on ∼500,000 genetic interactions of 350 mutants. We then apply the method to subunits Rpb1-Rpb2 of yeast RNA polymerase II and subunits RpoB-RpoC of bacterial RNA polymerase. The accuracy is comparable to that based on chemical cross-links; using restraints from both genetic interactions and cross-links further improves model accuracy and precision. The approach provides an efficient means to augment integrative structure determination with in vivo observations.

Original languageAmerican English
Article numbereaaz4910
Issue number6522
StatePublished - 11 Dec 2020
Externally publishedYes

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