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- PDB-9o65: Cryo-EM structure of SHOC2-KRAS-PP1CA (SKP) complex -

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Basic information

Entry
Database: PDB / ID: 9o65
TitleCryo-EM structure of SHOC2-KRAS-PP1CA (SKP) complex
Components
  • Isoform 2B of GTPase KRas
  • Leucine-rich repeat protein SHOC-2
  • Serine/threonine-protein phosphatase PP1-alpha catalytic subunit
KeywordsSIGNALING PROTEIN / KRAS / SHOC2 / PP1CA
Function / homology
Function and homology information


cellular response to growth hormone stimulus / regulation of glycogen catabolic process / positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled / negative regulation of neural precursor cell proliferation / PTW/PP1 phosphatase complex / protein phosphatase type 1 complex / glycogen granule / regulation of translational initiation in response to stress / nerve growth factor signaling pathway / RNA polymerase II promoter clearance ...cellular response to growth hormone stimulus / regulation of glycogen catabolic process / positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled / negative regulation of neural precursor cell proliferation / PTW/PP1 phosphatase complex / protein phosphatase type 1 complex / glycogen granule / regulation of translational initiation in response to stress / nerve growth factor signaling pathway / RNA polymerase II promoter clearance / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / cyclic-GMP-AMP transmembrane import across plasma membrane / cadherin binding involved in cell-cell adhesion / protein phosphatase 1 binding / protein phosphatase regulator activity / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / negative regulation of neuron differentiation / regulation of canonical Wnt signaling pathway / glycogen metabolic process / protein dephosphorylation / Phosphorylation and nuclear translocation of the CRY:PER:kinase complex / response to mineralocorticoid / GMP binding / Triglyceride catabolism / fibroblast growth factor receptor signaling pathway / protein-serine/threonine phosphatase / entrainment of circadian clock by photoperiod / LRR domain binding / negative regulation of transcription elongation by RNA polymerase II / response to isolation stress / response to gravity / telomere maintenance in response to DNA damage / myoblast proliferation / phosphatase activity / protein serine/threonine phosphatase activity / Maturation of hRSV A proteins / cardiac muscle cell proliferation / transition metal ion binding / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / regulation of MAPK cascade / RAS signaling downstream of NF1 loss-of-function variants / DARPP-32 events / RUNX3 regulates p14-ARF / positive regulation of glycogen biosynthetic process / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / ribonucleoprotein complex binding / Signalling to RAS / positive regulation of neuron differentiation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / positive regulation of Ras protein signal transduction / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / phosphoprotein phosphatase activity / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Tie2 Signaling / protein-membrane adaptor activity / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / liver development / GRB2 events in ERBB2 signaling / Downstream signal transduction / response to glucocorticoid / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / Downregulation of TGF-beta receptor signaling / small monomeric GTPase
Similarity search - Function
: / Serine-threonine protein phosphatase, N-terminal / Serine-threonine protein phosphatase N-terminal domain / : / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / : / Leucine-rich repeat region / Leucine-rich repeats, bacterial type ...: / Serine-threonine protein phosphatase, N-terminal / Serine-threonine protein phosphatase N-terminal domain / : / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / : / Leucine-rich repeat region / Leucine-rich repeats, bacterial type / Leucine-rich repeat, SDS22-like subfamily / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like / Small GTPase, Ras-type / Small GTPase Ras domain profile. / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Leucine-rich repeat profile. / Leucine-rich repeat / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Leucine-rich repeat domain superfamily / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / : / GTPase KRas / Serine/threonine-protein phosphatase PP1-alpha catalytic subunit / Leucine-rich repeat protein SHOC-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsFinci, L.I. / Bonsor, D.A. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)75N91019D00024 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.
Authors: Daniel A Bonsor / Lorenzo I Finci / Jacob R Potter / Lucy C Young / Vanessa E Wall / Ruby Goldstein de Salazar / Katie R Geis / Tyler Stephens / Joseph Finney / Dwight V Nissley / Frank ...Authors: Daniel A Bonsor / Lorenzo I Finci / Jacob R Potter / Lucy C Young / Vanessa E Wall / Ruby Goldstein de Salazar / Katie R Geis / Tyler Stephens / Joseph Finney / Dwight V Nissley / Frank McCormick / Dhirendra K Simanshu /
Abstract: RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2-RAS-PP1C complex. MRAS forms a high-affinity SHOC2- ...RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2-RAS-PP1C complex. MRAS forms a high-affinity SHOC2-MRAS-PP1C (SMP) complex, while canonical RAS isoforms (KRAS, HRAS, NRAS) form analogous but lower-affinity assemblies. Yet, cancers driven by oncogenic KRAS, HRAS, or NRAS remain strongly SHOC2-dependent, suggesting that these weaker complexes contribute to tumorigenesis. To elucidate how canonical RAS proteins form lower-affinity ternary complexes, the cryo-EM structure of the SHOC2-KRAS-PP1C (SKP) complex stabilized by Noonan syndrome mutations is described. The SKP architecture is similar to the SMP complex but forms fewer contacts and buries less surface area due to the absence of MRAS-specific structural features in KRAS that enhance complex stability. RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. These RAS inhibitors do not affect SMP formation because they do not bind MRAS. Since MRAS is upregulated in resistance to KRAS inhibition, we characterize a MRAS mutant capable of binding MRTX1133. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.
History
DepositionApr 11, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.1Feb 25, 2026Group: Data collection / Database references / Category: citation / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leucine-rich repeat protein SHOC-2
B: Isoform 2B of GTPase KRas
C: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,4567
Polymers121,8003
Non-polymers6564
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein Leucine-rich repeat protein SHOC-2 / Protein soc-2 homolog / Protein sur-8 homolog


Mass: 64954.840 Da / Num. of mol.: 1 / Mutation: M173I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHOC2, KIAA0862 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9UQ13
#2: Protein Isoform 2B of GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19300.824 Da / Num. of mol.: 1 / Mutation: Q61R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P01116, small monomeric GTPase
#3: Protein Serine/threonine-protein phosphatase PP1-alpha catalytic subunit / PP-1A


Mass: 37543.984 Da / Num. of mol.: 1 / Mutation: P50R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP1CA, PPP1A / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P62136, protein-serine/threonine phosphatase

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Non-polymers , 3 types, 4 molecules

#4: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn

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Details

Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Ternary complex of SHOC2, KRAS, and PP1CA / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.12 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMsodium chlorideNaCl1
31 mMTCEPC9H15O6P1
41 mMMagnesium ChlorideMgCl21
SpecimenConc.: 0.08 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GRAPHENE OXIDE / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2250 nm / Nominal defocus min: 750 nm
Image recordingElectron dose: 52.3 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2PHENIX1.20.1_4487model refinement
3Latitudeimage acquisition
5cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 518550
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 199681 / Symmetry type: POINT
RefinementHighest resolution: 3 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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