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- PDB-3cu8: Impaired binding of 14-3-3 to Raf1 is linked to Noonan and LEOPAR... -

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Basic information

Entry
Database: PDB / ID: 3cu8
TitleImpaired binding of 14-3-3 to Raf1 is linked to Noonan and LEOPARD syndrome
Components
  • 14-3-3 protein zeta/delta
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsPROTEIN BINDING / SIGNALING PROTEIN / 14-3-3 / zeta / adapter protein / cRaf1 / NOONAN syndrome / LEOPARD syndrome / Phosphoprotein
Function / homology
Function and homology information


death-inducing signaling complex assembly / Golgi reassembly / intermediate filament cytoskeleton organization / regulation of synapse maturation / NOTCH4 Activation and Transmission of Signal to the Nucleus / establishment of Golgi localization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...death-inducing signaling complex assembly / Golgi reassembly / intermediate filament cytoskeleton organization / regulation of synapse maturation / NOTCH4 Activation and Transmission of Signal to the Nucleus / establishment of Golgi localization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / negative regulation of protein localization to nucleus / Negative feedback regulation of MAPK pathway / KSRP (KHSRP) binds and destabilizes mRNA / GP1b-IX-V activation signalling / IFNG signaling activates MAPKs / ERBB2-ERBB3 signaling pathway / regulation of cell differentiation / face development / pseudopodium / somatic stem cell population maintenance / neurotrophin TRK receptor signaling pathway / thyroid gland development / Regulation of localization of FOXO transcription factors / extrinsic apoptotic signaling pathway via death domain receptors / Interleukin-3, Interleukin-5 and GM-CSF signaling / MAP kinase kinase kinase activity / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / cellular response to glucose starvation / negative regulation of protein-containing complex assembly / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Schwann cell development / type II interferon-mediated signaling pathway / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / RHO GTPases activate PKNs / negative regulation of TORC1 signaling / response to muscle stretch / activation of adenylate cyclase activity / myelination / CD209 (DC-SIGN) signaling / negative regulation of innate immune response / protein sequestering activity / regulation of ERK1 and ERK2 cascade / insulin-like growth factor receptor signaling pathway / thymus development / Translocation of SLC2A4 (GLUT4) to the plasma membrane / Deactivation of the beta-catenin transactivating complex / TP53 Regulates Metabolic Genes / Negative regulation of NOTCH4 signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / wound healing / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / MAP2K and MAPK activation / Stimuli-sensing channels / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / melanosome / MAPK cascade / Signaling by BRAF and RAF1 fusions / insulin receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / blood microparticle / regulation of apoptotic process / DNA-binding transcription factor binding / vesicle / mitochondrial outer membrane / transmembrane transporter binding / positive regulation of MAPK cascade / non-specific serine/threonine protein kinase / protein kinase activity / cadherin binding / negative regulation of cell population proliferation / protein phosphorylation / focal adhesion / protein serine kinase activity / protein serine/threonine kinase activity / glutamatergic synapse / apoptotic process / ubiquitin protein ligase binding / negative regulation of apoptotic process / protein kinase binding / Golgi apparatus / negative regulation of transcription by RNA polymerase II / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular space / RNA binding / extracellular exosome / nucleoplasm
Similarity search - Function
14-3-3 domain / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Delta-Endotoxin; domain 1 / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. ...14-3-3 domain / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Delta-Endotoxin; domain 1 / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
PROPANOIC ACID / RAF proto-oncogene serine/threonine-protein kinase / 14-3-3 protein zeta/delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsSchumacher, B. / Weyand, M. / Kuhlmann, J. / Ottmann, C.
CitationJournal: Mol. Cell. Biol. / Year: 2010
Title: Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling.
Authors: Molzan, M. / Schumacher, B. / Ottmann, C. / Baljuls, A. / Polzien, L. / Weyand, M. / Thiel, P. / Rose, R. / Rose, M. / Kuhenne, P. / Kaiser, M. / Rapp, U.R. / Kuhlmann, J. / Ottmann, C.
History
DepositionApr 16, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0May 5, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Jun 7, 2017Group: Database references
Revision 1.3Oct 25, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 14-3-3 protein zeta/delta
B: 14-3-3 protein zeta/delta
P: RAF proto-oncogene serine/threonine-protein kinase
Q: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,8377
Polymers57,7144
Non-polymers1233
Water3,531196
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4960 Å2
ΔGint-42 kcal/mol
Surface area22520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.400, 83.840, 111.650
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein 14-3-3 protein zeta/delta / 14-3-3 zeta adapter protein / Protein kinase C inhibitor protein 1 / KCIP-1


Mass: 27777.092 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YWHAZ / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P63104
#2: Protein/peptide RAF proto-oncogene serine/threonine-protein kinase / Raf-1 / C-RAF / cRaf


Mass: 1080.046 Da / Num. of mol.: 2 / Fragment: Phosphorylated cRaf1 peptide / Source method: obtained synthetically
Details: Raf1pSer259 peptide (NH2-255QRSTpSTPNVHA265-COOH) was synthesized by Biosyntan (Berlin, Germany).
Source: (synth.) Homo sapiens (human)
References: UniProt: P04049, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-PPI / PROPANOIC ACID / Propionic acid


Mass: 74.079 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 196 / Source method: isolated from a natural source / Formula: H2O

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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: 2.94 Å3/Da / Density % sol: 58.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1M (Sodium propionate, sodium cacodylate, BIS-TRIS propane), 27% PEG 1500, 2mM DTT, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97809 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 25, 2007
RadiationMonochromator: LN2 cooled fixed-exit Si(111) monochromator, Sagittal-horizontal; Dynamically bendable mirror, Meridional-vertical
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97809 Å / Relative weight: 1
ReflectionResolution: 2.4→15 Å / Num. all: 27180 / Num. obs: 27180 / % possible obs: 99.8 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 4.95 % / Rmerge(I) obs: 0.052 / Rsym value: 0.2044
Reflection shellResolution: 2.4→2.5 Å / Redundancy: 5 % / Rmerge(I) obs: 0.416 / Mean I/σ(I) obs: 4.02 / Num. unique all: 3084 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.4.0067refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→15 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.91 / SU B: 13.344 / SU ML: 0.16 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.29 / ESU R Free: 0.248 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25901 1353 5 %RANDOM
Rwork0.18836 ---
all0.19192 25710 --
obs0.19192 25710 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 44.642 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å20 Å20 Å2
2--1.96 Å20 Å2
3----1.84 Å2
Refinement stepCycle: LAST / Resolution: 2.4→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3730 0 7 196 3933
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0223797
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9721.9725126
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3765473
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.31625.246183
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.66415.043699
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7141523
X-RAY DIFFRACTIONr_chiral_restr0.1540.2579
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022829
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9581.52368
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.86123788
X-RAY DIFFRACTIONr_scbond_it3.42231429
X-RAY DIFFRACTIONr_scangle_it5.4314.51336
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.461 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.389 97 -
Rwork0.254 1844 -
obs--100 %
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)
11.6009-0.26660.9031.5934-0.25221.5259-0.0644-0.0250.11440.13610.0275-0.182-0.26320.12230.0368-0.0797-0.01240.0011-0.1041-0.0216-0.124352.9870.81266.4076
22.25910.46720.44831.63240.26431.6139-0.09540.04530.1502-0.02060.00160.2392-0.1931-0.20830.0938-0.13150.09530.0162-0.10650.0076-0.023218.57421.638-10.4565
39.1247-2.8817-5.85348.09341.24256.5899-0.0407-0.09220.10910.09710.12090.1904-0.1622-0.0754-0.0802-0.0653-0.0142-0.0084-0.0303-0.0097-0.034848.7058-5.75476.4714
49.52473.0463-4.06866.0034-2.20372.0062-0.0752-0.1826-0.25820.1808-0.3923-0.1237-0.04160.43810.4675-0.06440.02920.0341-0.0150.00040.006220.6645-5.6475-7.4705
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA2 - 2302 - 230
2X-RAY DIFFRACTION2BB1 - 2301 - 230
3X-RAY DIFFRACTION3PC256 - 2641 - 9
4X-RAY DIFFRACTION4QD256 - 2631 - 8

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