MAPK variant effect atlas
Proteins / HGFR

HGFR

Hepatocyte growth factor receptor · gene MET

Receptor tyrosine kinase UniProt P08581 HSP90 client (literature): weak 3D structure ↓ 2 interaction partners · volcano ↗
Mutagenized 955–1390Kinase 1082–1343Kinase11,390 aagrey box: mutagenized region

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

8,958 variantsmissense decreased 33% · increased 2%124 dominant negative variants
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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 960 980 1000 1020 1040 1060 1080 1100 1120 1140 1160 1180 1200 1220 1240 1260 1280 1300 1320 1340 1360 1380 0.09 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 · HGFR alone

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Interfaces of HGFR

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
HGFR
PTKc_MET_Ron #2
PDB+0.654.6e-14-0.329.7e-0410supportedStructure ↗
HGFR
PTKc_MET_Ron #3
PDB+0.651.4e-11-0.320.0029supportedStructure ↗
HGF
PTKc_MET_Ron
AF-M-0.521.8e-07+0.839.6e-114supportedStructure ↗
HGFR
PTKc_MET_Ron #5
PDB-0.571.8e-08+0.492.8e-087supportedStructure ↗
HGFR
PTKc_MET_Ron
PDB+0.323.6e-04-0.363.6e-057supportedStructure ↗
HGFR
PTKc_MET_Ron #4
PDB-0.301.3e-04+0.205.9e-049supportedStructure ↗
HGF
res 1306-1357
AF-M+0.360.207+0.248.5e-044supportedStructure ↗