MAPK variant effect atlas
Proteins / ERBB2

ERBB2

Receptor tyrosine-protein kinase erbB-2

Receptor tyrosine kinase UniProt P04626 HSP90 client (literature): strong 3D structure ↓ 23 interaction partners · volcano ↗
Mutagenized 686–1255Kinase 720–987Kinase11,255 aagrey box: mutagenized region

MAPK pathway activity (phosphorylated ERK2 reporter) under basal conditions. Scores are WT-relative: 1 = wild type.

11,132 variantsmissense decreased 38% · increased 7%45 dominant negative variants
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 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.
Fraction dominant-negative
0%25%50%75%100%
Fraction of variants at this position called dominant negative: basal pathway activity below the empty-vector threshold (basal activity only).
Domain Secondary structure Relative SASA pLDDT Curated feature Annotated interface Active site Inter-domain contact HSP90 contact CDC37 contact Fraction decreased Fraction increased Fraction dominant-negative Interface A V I L G F Y W C M P S T N Q D E H K R * -
Kinase 700 720 740 760 780 800 820 840 860 880 900 920 940 960 980 1000 1020 1040 1060 1080 1100 1120 1140 1160 1180 1200 1220 1240 0.36 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 · ERBB2 alone

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Interfaces of ERBB2

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
VAV1
PTKc_HER2 #2
RF2-PPI-0.901.2e-33+0.070.4577supportedStructure ↗
SH2D3CRF2-PPI-0.831.6e-32+0.510.0029supportedStructure ↗
MEPCERF2-PPI+0.342.3e-26+0.225.8e-0511supportedStructure ↗
CBLCRF2-PPI+0.385.7e-25+0.214.2e-048supportedStructure ↗
JMJD4RF2-PPI+0.376.0e-25+0.287.6e-068supportedStructure ↗
CPNE3RF2-PPI+0.362.1e-21+0.110.01314supportedStructure ↗
LRPPRCRF2-PPI+0.384.7e-21+0.267.2e-047supportedStructure ↗
NXT1RF2-PPI+0.449.7e-18+0.294.7e-046supportedStructure ↗
SOCS3
PTKc_HER2
AF-M-0.711.5e-16+1.121.3e-135supportedStructure ↗
VAV3RF2-PPI-0.657.6e-14-0.010.4516supportedStructure ↗
ERRFI1AF-M-0.291.2e-11+0.290.01724supportedStructure ↗
SOCS3
res 948-1141
AF-M-0.010.029+0.752.0e-116supportedStructure ↗
LRRC15RF2-PPI+0.402.9e-11+0.290.0093supportedStructure ↗
ERBB3RF2-PPI+0.070.353+0.282.7e-0825supportedStructure ↗
PCAF-M-0.406.0e-08+0.481.7e-0412supportedStructure ↗
ERBB4RF2-PPI+0.060.150+0.288.4e-0822supportedStructure ↗
MATKRF2-PPI+0.282.1e-07+0.130.0249supportedStructure ↗
CD44RF2-PPI-0.584.0e-07-0.290.0075supportedStructure ↗
TIMM50RF2-PPI+0.273.7e-06+0.170.0664supportedStructure ↗
EGFRAF-M+0.040.008+0.234.4e-0522supportedStructure ↗
VAV1
PTKc_HER2
RF2-PPI-0.180.229-0.499.5e-044supportedStructure ↗
IQGAP1RF2-PPI-0.300.001+0.170.5579supportedStructure ↗
VAV2RF2-PPI-0.280.003+0.240.1598supportedStructure ↗
EGLN3RF2-PPI+0.610.224-0.380.0183supportedStructure ↗
ANK1RF2-PPI-0.270.025+0.130.1604supportedStructure ↗
ERBB4AF-M+0.050.002+0.090.08819not supportedStructure ↗
ERBB3AF-M+0.060.014+0.110.02119not supportedStructure ↗
GRM1AF-M-0.090.027+0.020.6387not supportedStructure ↗
NOTCH2
PTKc_HER2 #2
RF2-PPI-0.160.257+0.240.5235not supportedStructure ↗
NOTCH2
PTKc_HER2
RF2-PPI-0.070.697+0.040.9766not supportedStructure ↗