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- PDB-7t7a: Crystal Structure of Human SHOC2: A Leucine-Rich Repeat Protein -

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Basic information

Entry
Database: PDB / ID: 7t7a
TitleCrystal Structure of Human SHOC2: A Leucine-Rich Repeat Protein
ComponentsLeucine-rich repeat protein SHOC-2
KeywordsSTRUCTURAL PROTEIN / scaffold / leucine-rich
Function / homology
Function and homology information


cellular response to growth hormone stimulus / protein phosphatase type 1 complex / negative regulation of neural precursor cell proliferation / cyclic-GMP-AMP transmembrane import across plasma membrane / nerve growth factor signaling pathway / protein phosphatase regulator activity / protein phosphatase 1 binding / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of Ras protein signal transduction ...cellular response to growth hormone stimulus / protein phosphatase type 1 complex / negative regulation of neural precursor cell proliferation / cyclic-GMP-AMP transmembrane import across plasma membrane / nerve growth factor signaling pathway / protein phosphatase regulator activity / protein phosphatase 1 binding / 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 / cytoplasm / cytosol
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
NITRATE ION / Leucine-rich repeat protein SHOC-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsHajian, B. / Lemke, C. / Kwon, J. / Bian, Y. / Fuller, C. / Aguirre, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nature / Year: 2022
Title: Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.
Authors: Jason J Kwon / Behnoush Hajian / Yuemin Bian / Lucy C Young / Alvaro J Amor / James R Fuller / Cara V Fraley / Abbey M Sykes / Jonathan So / Joshua Pan / Laura Baker / Sun Joo Lee / Douglas ...Authors: Jason J Kwon / Behnoush Hajian / Yuemin Bian / Lucy C Young / Alvaro J Amor / James R Fuller / Cara V Fraley / Abbey M Sykes / Jonathan So / Joshua Pan / Laura Baker / Sun Joo Lee / Douglas B Wheeler / David L Mayhew / Nicole S Persky / Xiaoping Yang / David E Root / Anthony M Barsotti / Andrew W Stamford / Charles K Perry / Alex Burgin / Frank McCormick / Christopher T Lemke / William C Hahn / Andrew J Aguirre /
Abstract: Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase ...Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .
History
DepositionDec 14, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 17, 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.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 21, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Leucine-rich repeat protein SHOC-2
B: Leucine-rich repeat protein SHOC-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,3314
Polymers111,2452
Non-polymers862
Water9,908550
1
A: Leucine-rich repeat protein SHOC-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6472
Polymers55,6221
Non-polymers241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Leucine-rich repeat protein SHOC-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6842
Polymers55,6221
Non-polymers621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.930, 103.030, 121.090
Angle α, β, γ (deg.)90.000, 101.928, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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


Mass: 55622.324 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHOC2, KIAA0862
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q9UQ13
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: NO3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 550 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.52 Å3/Da / Density % sol: 51.23 %
Crystal growTemperature: 281 K / Method: vapor diffusion, hanging drop
Details: 400 mM magnesium nitrate 200 mM Tris PH 8.5 23-30% PEG 4K

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Data collection

DiffractionMean temperature: 193 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Dec 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 1.79→48.5 Å / Num. obs: 99833 / % possible obs: 96.8 % / Redundancy: 4.2 % / Biso Wilson estimate: 33.94 Å2 / CC1/2: 0.8 / Net I/σ(I): 2.2
Reflection shellResolution: 1.79→1.85 Å / Num. unique obs: 9677 / CC1/2: 0.44

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Processing

Software
NameVersionClassification
Blu-Icedata collection
XDSdata scaling
MOSFLMdata reduction
Cootmodel building
PHENIXV1.0refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.79→48.5 Å / SU ML: 0.2536 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.8682
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2407 1999 2 %
Rwork0.2045 97833 -
obs0.2052 99832 96.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.57 Å2
Refinement stepCycle: LAST / Resolution: 1.79→48.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7690 0 5 550 8245
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00777870
X-RAY DIFFRACTIONf_angle_d1.004310690
X-RAY DIFFRACTIONf_chiral_restr0.05761308
X-RAY DIFFRACTIONf_plane_restr0.0081369
X-RAY DIFFRACTIONf_dihedral_angle_d5.79921057
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.79-1.840.36511380.3066733X-RAY DIFFRACTION93.13
1.84-1.890.29661420.28646947X-RAY DIFFRACTION97.22
1.89-1.940.32921420.29246996X-RAY DIFFRACTION97.05
1.94-2.010.28281430.2717018X-RAY DIFFRACTION97.68
2.01-2.080.26831430.24826999X-RAY DIFFRACTION97.44
2.08-2.160.31011450.23637087X-RAY DIFFRACTION98.07
2.16-2.260.2911440.24447001X-RAY DIFFRACTION97.81
2.26-2.380.27331450.23687128X-RAY DIFFRACTION98.08
2.38-2.530.30591430.23997017X-RAY DIFFRACTION98.06
2.53-2.720.29331460.23657103X-RAY DIFFRACTION98.09
2.72-30.22971420.22776999X-RAY DIFFRACTION96.98
3-3.430.26921430.2216954X-RAY DIFFRACTION96.15
3.43-4.320.20671400.16216860X-RAY DIFFRACTION94.56
4.32-48.50.17311430.1546991X-RAY DIFFRACTION95.31

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