MAPK variant effect atlas
Proteins / BRAF

BRAF

Serine/threonine-protein kinase B-raf

RAF kinase UniProt P15056 HSP90 client (literature): weak 3D structure ↓ 19 interaction partners · volcano ↗
Mutagenized 2–456Mutagenized 457–766BSD 41–106BSDRBD 155–227RBDCRD 234–280Kinase 457–717Kinase1766 aagrey box: mutagenized region

Abundance under HSP90 inhibition (pimitespib). The HSP90 calls compare each variant's inhibited and untreated abundance. Scores are WT-relative: 1 = wild type.

15,703 variantsmissense decreased 25% · increased 2%HSP90-dependent 56% of missense & deletionsbuffered 15% · poorly buffered 11% · WT-like or increased 73%
Other cells fade; highlighted cells are outlined.
Annotation tracks
Structure
Function
Chaperone
Variant effect
Track legend & definitions
Secondary structure
alpha helix3-10 helixpi helixbeta strandbeta bridgeturnbendno_ss
DSSP assignment on the reference structure.
Relative SASA
0.000.250.500.751.00
Side-chain solvent accessibility (0 = buried, 1 = fully exposed). The pipeline calls a residue surface-exposed above 0.25.
pLDDT
50.062.575.087.5100.0
AlphaFold per-residue confidence. The analysis drops residues below 60.
Curated feature
Protein-protein interfaceCatalytic / active siteLigand / substrate pocketRegulatory elementOther annotation
UniProt / literature annotation, coloured by class. Red marks a curated protein-protein interface — the independent comparison for our predicted interfaces.
Annotated interface
yesno
Curated protein-interface residue, independent of any structure prediction in this study.
Active site
yesno
Curated catalytic / active-site residue.
Inter-domain contact
yesno
Residue contacting another domain of the same protein (all-atom), so a variant effect there may be intramolecular rather than at a PPI.
HSP90 contact
TrueFalseUnknown
Contacts HSP90 in the chaperone-client cryo-EM structures ('Unknown' where the protein was not mapped).
CDC37 contact
TrueFalseUnknown
Contacts CDC37. These positions report kinase foldability rather than a canonical binding surface.
Fraction buffered
0%25%50%75%100%
Fraction of variants at this position that are buffered: wild-type-like untreated but decreased under HSP90 inhibition (HSP90i condition only).
Fraction HSP90-dependent
0%25%50%75%100%
Fraction of variants at this position whose abundance falls under HSP90 inhibition by at least the wild-type-to-synonymous gap (the paper's dependence call; HSP90i condition only).
Fraction decreased
0%25%50%75%100%
Fraction of variants at this position classified decreased in this assay (2.5th-percentile rule).
Fraction increased
0%25%50%75%100%
Fraction of variants at this position classified increased in this assay.
Domain Secondary structure Relative SASA pLDDT Curated feature Annotated interface Active site Inter-domain contact HSP90 contact CDC37 contact Fraction buffered Fraction HSP90-dependent Fraction decreased Fraction increased Interface A V I L G F Y W C M P S T N Q D E H K R * -
BSD RBD CRD Kinase 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460 480 500 520 540 560 580 600 620 640 660 680 700 720 740 760 0.28 1.00 2.00
Click a position for its interactions and annotations — ■ the Interface strip marks positions in ≥1 supported interface (darker = more partners)

Structure · BRAF alone

Loading 3D viewer…

Interfaces of BRAF

One row per interface: complexes of the same pair and source whose interfaces overlap (IoU ≥ 0.3) are merged, as in the Fig. 6c,d volcano plots (median Cohen's d; q from the geometric-mean p). Supported: at least one complex with q < 0.05 and |d| ≥ 0.2 in either basal assay.

PartnerSourceActivity dq Abundance dqInterface positionsSupported
KSR2
STKc_Raf
RF2-PPI-0.432.9e-68+0.815.7e-2212supportedStructure ↗
BRAF
STKc_Raf
PDB-0.381.0e-50+0.782.7e-1711supportedStructure ↗
ARAFAF-M-0.432.1e-49+0.829.3e-2011supportedStructure ↗
KSR2AF-M-0.404.1e-48+0.514.6e-1120supportedStructure ↗
CRAFAF-M-0.432.1e-42+0.827.2e-1710supportedStructure ↗
ITCHAF-M+1.012.5e-39-0.577.0e-109supportedStructure ↗
KSR1AF-M-0.382.4e-37+0.483.7e-0921supportedStructure ↗
CDC37PDB-0.253.1e-37-0.612.9e-0611supportedStructure ↗
KSR1RF2-PPI-0.361.6e-36+0.453.7e-0921supportedStructure ↗
YWHAZ
res 241-719
PDB+1.122.7e-29-0.618.1e-1610supportedStructure ↗
MEK2RF2-PPI+0.264.4e-26+0.030.6099supportedStructure ↗
MAP2K3AF-M-0.043.5e-25+0.180.0199supportedStructure ↗
MAP2K6AF-M-0.057.2e-24+0.210.0098supportedStructure ↗
MEK1PDB+0.069.4e-23+0.060.03317supportedStructure ↗
STK11AF-M-0.113.9e-21+0.230.00211supportedStructure ↗
STK11RF2-PPI-0.133.9e-16+0.240.00210supportedStructure ↗
V9P4T4PDB+1.111.4e-13-0.605.9e-1311supportedStructure ↗
RAP1AAF-M-0.236.9e-05+0.351.9e-048supportedStructure ↗
KRASPDB-0.291.9e-04+0.359.7e-046supportedStructure ↗
BRAF
STKc_Raf #2
PDB+0.480.009-0.222.3e-0415supportedStructure ↗
RAP1BAF-M-0.210.002+0.320.0017supportedStructure ↗
MRASAF-M-0.210.009+0.310.00210supportedStructure ↗
KSR2
res 49-77
RF2-PPI-0.280.033-0.020.53410supportedStructure ↗
HRASAF-M+0.490.046-0.150.16711supportedStructure ↗
MEK1RF2-PPI-0.041.9e-25+0.100.18210not supportedStructure ↗
MEK2AF-M-0.096.9e-20+0.120.06912not supportedStructure ↗
MEK1AF-M-0.079.7e-19+0.130.06110not supportedStructure ↗
A0A1B0GUL7RF2-PPI-0.085.6e-16+0.120.1588not supportedStructure ↗
MAP2K7AF-M-0.046.7e-15+0.150.1165not supportedStructure ↗
BRAF
STKc_Raf #3
PDB-0.150.002-0.010.79513not supportedStructure ↗
YWHAZ
res 239-735
PDB-0.070.045+0.090.3887not supportedStructure ↗
NRASAF-M+0.420.127-0.140.88313not supportedStructure ↗
HSP90AB1PDB+0.230.834-0.050.2154not supportedStructure ↗
KRASAF-M+0.320.295-0.070.44512not supportedStructure ↗
YWHAZ
STKc_Raf
PDB-0.210.320-0.160.3405not supportedStructure ↗