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- PDB-7sd1: Crystal structure of SHOC2 -

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Basic information

Entry
Database: PDB / ID: 7sd1
TitleCrystal structure of SHOC2
ComponentsLeucine-rich repeat protein SHOC-2
KeywordsSIGNALING PROTEIN / PP1C / RAS / Scaffold
Function / homology
Function and homology information


cellular response to growth hormone stimulus / protein phosphatase type 1 complex / negative regulation of neural precursor cell proliferation / nerve growth factor signaling pathway / protein phosphatase 1 binding / protein phosphatase regulator activity / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of Ras protein signal transduction / negative regulation of neuron differentiation ...cellular response to growth hormone stimulus / protein phosphatase type 1 complex / negative regulation of neural precursor cell proliferation / nerve growth factor signaling pathway / protein phosphatase 1 binding / protein phosphatase regulator activity / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of Ras protein signal transduction / negative regulation of neuron differentiation / fibroblast growth factor receptor signaling pathway / positive regulation of neuron differentiation / RAF activation / positive regulation of neuron projection development / protein phosphatase binding / Ras protein signal transduction / signal transduction / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Leucine-rich repeats, bacterial type / Leucine-rich repeat, SDS22-like subfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Leucine-rich repeat protein SHOC-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.19 Å
AuthorsLiau, N.P.D. / Hymowitz, S.G. / Sudhamsu, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nature / Year: 2022
Title: Structural basis for SHOC2 modulation of RAS signalling.
Authors: Nicholas P D Liau / Matthew C Johnson / Saeed Izadi / Luca Gerosa / Michal Hammel / John M Bruning / Timothy J Wendorff / Wilson Phung / Sarah G Hymowitz / Jawahar Sudhamsu /
Abstract: The RAS-RAF pathway is one of the most commonly dysregulated in human cancers. Despite decades of study, understanding of the molecular mechanisms underlying dimerization and activation of the kinase ...The RAS-RAF pathway is one of the most commonly dysregulated in human cancers. Despite decades of study, understanding of the molecular mechanisms underlying dimerization and activation of the kinase RAF remains limited. Recent structures of inactive RAF monomer and active RAF dimer bound to 14-3-3 have revealed the mechanisms by which 14-3-3 stabilizes both RAF conformations via specific phosphoserine residues. Prior to RAF dimerization, the protein phosphatase 1 catalytic subunit (PP1C) must dephosphorylate the N-terminal phosphoserine (NTpS) of RAF to relieve inhibition by 14-3-3, although PP1C in isolation lacks intrinsic substrate selectivity. SHOC2 is as an essential scaffolding protein that engages both PP1C and RAS to dephosphorylate RAF NTpS, but the structure of SHOC2 and the architecture of the presumptive SHOC2-PP1C-RAS complex remain unknown. Here we present a cryo-electron microscopy structure of the SHOC2-PP1C-MRAS complex to an overall resolution of 3 Å, revealing a tripartite molecular architecture in which a crescent-shaped SHOC2 acts as a cradle and brings together PP1C and MRAS. Our work demonstrates the GTP dependence of multiple RAS isoforms for complex formation, delineates the RAS-isoform preference for complex assembly, and uncovers how the SHOC2 scaffold and RAS collectively drive specificity of PP1C for RAF NTpS. Our data indicate that disease-relevant mutations affect complex assembly, reveal the simultaneous requirement of two RAS molecules for RAF activation, and establish rational avenues for discovery of new classes of inhibitors to target this pathway.
History
DepositionSep 29, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jul 27, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Sep 21, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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: Leucine-rich repeat protein SHOC-2
C: Leucine-rich repeat protein SHOC-2
D: Leucine-rich repeat protein SHOC-2


Theoretical massNumber of molelcules
Total (without water)260,6284
Polymers260,6284
Non-polymers00
Water0
1
A: Leucine-rich repeat protein SHOC-2


Theoretical massNumber of molelcules
Total (without water)65,1571
Polymers65,1571
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Leucine-rich repeat protein SHOC-2


Theoretical massNumber of molelcules
Total (without water)65,1571
Polymers65,1571
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Leucine-rich repeat protein SHOC-2


Theoretical massNumber of molelcules
Total (without water)65,1571
Polymers65,1571
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Leucine-rich repeat protein SHOC-2


Theoretical massNumber of molelcules
Total (without water)65,1571
Polymers65,1571
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)168.630, 201.830, 233.770
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

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


Mass: 65156.969 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHOC2, KIAA0862 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UQ13

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.82 Å3/Da / Density % sol: 72.84 %
Crystal growTemperature: 289 K / Method: vapor diffusion / pH: 8.5 / Details: 100 mM Tris 8.5, 200 mM MgCl2, 14% (w/v) PEG 4000

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 3.19→49.13 Å / Num. obs: 444449 / % possible obs: 97.79 % / Redundancy: 6.7 % / Biso Wilson estimate: 117.54 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.1765 / Rpim(I) all: 0.07335 / Rrim(I) all: 0.1915 / Net I/σ(I): 8.95
Reflection shellResolution: 3.192→3.39 Å / Rmerge(I) obs: 3.37 / Mean I/σ(I) obs: 0.51 / Num. unique obs: 10510 / CC1/2: 0.294

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Processing

Software
NameVersionClassification
PHENIX1.19.1-4122_finalrefinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4U06

4u06


Resolution: 3.19→49.13 Å / SU ML: 0.61 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 29.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2378 3683 2.99 %
Rwork0.2085 119688 -
obs0.2094 123371 96.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 260.2 Å2 / Biso mean: 120.8103 Å2 / Biso min: 52.93 Å2
Refinement stepCycle: final / Resolution: 3.19→49.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15721 0 0 0 15721
Num. residues----1997
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 26

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.19-3.230.5598520.47562016206843
3.23-3.280.38871300.40434091422185
3.28-3.320.41451440.38084464460892
3.32-3.370.41021400.38144590473096
3.37-3.430.37971410.3654565470696
3.43-3.480.34391440.35454705484999
3.48-3.540.40111450.342147374882100
3.54-3.610.33041440.315548094953100
3.61-3.680.2861470.29247664913100
3.68-3.750.30391470.27724746489399
3.75-3.830.30721440.273747754919100
3.83-3.920.36311490.265347474896100
3.92-4.020.28421440.248747914935100
4.02-4.130.27731470.20747574904100
4.13-4.250.24191470.19947734920100
4.25-4.390.23791490.190748004949100
4.39-4.540.22111430.182547564899100
4.55-4.730.2131470.174547824929100
4.73-4.940.17561430.1744736487999
4.94-5.20.21981480.177447854933100
5.2-5.530.24381470.19447584905100
5.53-5.950.2281450.203447884933100
5.95-6.550.24471510.192748064957100
6.55-7.50.2271460.18134729487599
7.5-9.430.21241520.199247684920100
9.43-49.130.14121470.13024648479597
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3743-1.1147-0.49181.8530.96711.7529-0.2437-0.25990.16360.40460.2923-0.22560.1071-0.0434-0.05350.75230.1105-0.02280.60250.13020.8067-24.1777-75.0417-27.2987
20.8762-0.68950.44821.9211-0.08151.096-0.2085-0.4827-0.22630.33650.3690.22340.2439-0.0018-0.16570.7010.19990.08370.84260.10490.7438-70.2591-32.2123-32.9266
31.6161-0.63951.12851.2186-0.48611.48490.17290.2154-0.2159-0.1938-0.0310.29880.05890.0373-0.14590.70380.1110.10780.73390.07980.8383-29.2047-80.3508-27.9047
42.6565-1.64230.22182.2658-0.24560.8531-0.3075-0.44760.32740.31170.3764-0.1059-0.0235-0.1051-0.07010.82240.20380.010.78080.13310.8445-65.5676-27.4885-32.7992
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'A' and resid 87 through 581)A87 - 581
2X-RAY DIFFRACTION2(chain 'B' and resid 88 through 582)B88 - 582
3X-RAY DIFFRACTION3(chain 'C' and resid 85 through 585)C85 - 585
4X-RAY DIFFRACTION4(chain 'D' and resid 87 through 585)D87 - 585

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