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.
ID: efoFATG74
Submitter: Shu-Ching Ou
Submission Date: March 12, 2019, 4:58 p.m.
Version: 1
Scripts and original data can be found in: https://github.com/lehner-lab/FOS_JUN_trans_epistasis
Colors: | D | E | R | H | K | S | T | N | Q | A | V | I | L | M | F | Y | W | C | G | P |
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Structure ID | Release Date | Resolution | Structure Title |
---|---|---|---|
2H7H | 2006-06-02T00:00:00+0000 | 2.3 | Crystal structure of the JUN BZIP homodimer complexed with AP-1 DNA |
2WT7 | 2009-09-11T00:00:00+0000 | 2.3 | Crystal structure of the bZIP heterodimeric complex MafB:cFos bound to DNA |
1A02 | 1997-12-08T00:00:00+0000 | 2.7 | STRUCTURE OF THE DNA BINDING DOMAINS OF NFAT, FOS AND JUN BOUND TO DNA |
1FOS | 1995-03-07T00:00:00+0000 | 3.05 | TWO HUMAN C-FOS:C-JUN:DNA COMPLEXES |
1S9K | 2004-02-04T00:00:00+0000 | 3.1 | Crystal Structure of Human NFAT1 and Fos-Jun on the IL-2 ARRE1 Site |
1A02 | 1997-12-08T00:00:00+0000 | 2.7 | STRUCTURE OF THE DNA BINDING DOMAINS OF NFAT, FOS AND JUN BOUND TO DNA |
1FOS | 1995-03-07T00:00:00+0000 | 3.05 | TWO HUMAN C-FOS:C-JUN:DNA COMPLEXES |
1JNM | 2001-07-24T00:00:00+0000 | 2.2 | Crystal Structure of the Jun/CRE Complex |
1JUN | 1995-12-19T00:00:00+0000 | 0 | NMR STUDY OF C-JUN HOMODIMER |
1S9K | 2004-02-04T00:00:00+0000 | 3.1 | Crystal Structure of Human NFAT1 and Fos-Jun on the IL-2 ARRE1 Site |
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 |