The genetic landscape of a physical interaction.


Abstract

A key question in human genetics and evolutionary biology is how mutations in different genes combine to alter phenotypes. Efforts to systematically map genetic interactions have mostly made use of gene deletions. However, most genetic variation consists of point mutations of diverse and difficult to predict effects. Here, by developing a new sequencing-based protein interaction assay - deepPCA - we quantified the effects of >120,000 pairs of point mutations on the formation of the AP-1 transcription factor complex between the products of the FOS and JUN proto-oncogenes. Genetic interactions are abundant both in cis (within one protein) and trans (between the two molecules) and consist of two classes - interactions driven by thermodynamics that can be predicted using a three-parameter global model, and structural interactions between proximally located residues. These results reveal how physical interactions generate quantitatively predictable genetic interactions.

Submission Details

ID: efoFATG74

Submitter: Shu-Ching Ou

Submission Date: March 12, 2019, 4:58 p.m.

Version: 1

Publication Details
Diss G;Lehner B,Elife (2018) The genetic landscape of a physical interaction. PMID:29638215
Additional Information

Scripts and original data can be found in: https://github.com/lehner-lab/FOS_JUN_trans_epistasis

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1JUN 1996-06-20 NMR STUDY OF C-JUN HOMODIMER
5T01 2017-03-01 1.89 Human c-Jun DNA binding domain homodimer in complex with methylated DNA
5FV8 2017-06-07 1.99 Structure of cJun-FosW coiled coil complex.
1JNM 2003-06-03 2.2 Crystal Structure of the Jun/CRE Complex
2WT7 2010-09-29 2.3 Crystal structure of the bZIP heterodimeric complex MafB:cFos bound to DNA
2H7H 2007-06-12 2.3 Crystal structure of the JUN BZIP homodimer complexed with AP-1 DNA
1A02 1998-05-27 2.7 STRUCTURE OF THE DNA BINDING DOMAINS OF NFAT, FOS AND JUN BOUND TO DNA
1T2K 2004-11-16 3.0 Structure Of The DNA Binding Domains Of IRF3, ATF-2 and Jun Bound To DNA
1FOS 1995-07-10 3.05 TWO HUMAN C-FOS:C-JUN:DNA COMPLEXES
1S9K 2005-06-14 3.1 Crystal Structure of Human NFAT1 and Fos-Jun on the IL-2 ARRE1 Site

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
196.8 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P29176 FOSX_MSVFR
193.6 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein Q9Z2Q8 FOS_CRIGR
196.4 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein O02761 FOS_SHEEP
196.4 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein O97930 FOS_PIG
196.2 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein O77628 FOS_BOVIN
196.2 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein Q8HZP6 FOS_FELCA
196.2 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P01100 FOS_HUMAN
196.2 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein O88479 FOS_MESAU
196.2 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P01101 FOS_MOUSE
196.2 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein Q56TN0 FOS_PHORO
196.2 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P12841 FOS_RAT
192.8 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein Q56TT7 FOS_PHOCM
192.6 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P01102 FOS_MSVFB
181.0 E,G P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P53450 FOS_TAKRU
200.0 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P05411 JUN_AVIS1
196.8 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein O77627 JUN_BOVIN
196.8 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P18870 JUN_CHICK
196.8 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P12981 JUN_COTJA
196.8 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P05412 JUN_HUMAN
196.8 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P05627 JUN_MOUSE
196.8 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P56432 JUN_PIG
196.8 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P17325 JUN_RAT
196.8 F,H P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein P54864 JUN_SERCA