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- PDB-6ew1: Crystal structure of the Filamin A Ig-like domains 3-5 mutant P637Q -

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Basic information

Entry
Database: PDB / ID: 6ew1
TitleCrystal structure of the Filamin A Ig-like domains 3-5 mutant P637Q
ComponentsFilamin-A
KeywordsCELL ADHESION / Actin binding protein
Function / homology
Function and homology information


regulation of membrane repolarization during atrial cardiac muscle cell action potential / regulation of membrane repolarization during cardiac muscle cell action potential / establishment of Sertoli cell barrier / Myb complex / glycoprotein Ib-IX-V complex / formation of radial glial scaffolds / adenylate cyclase-inhibiting dopamine receptor signaling pathway / positive regulation of integrin-mediated signaling pathway / cytoplasmic sequestering of protein / tubulin deacetylation ...regulation of membrane repolarization during atrial cardiac muscle cell action potential / regulation of membrane repolarization during cardiac muscle cell action potential / establishment of Sertoli cell barrier / Myb complex / glycoprotein Ib-IX-V complex / formation of radial glial scaffolds / adenylate cyclase-inhibiting dopamine receptor signaling pathway / positive regulation of integrin-mediated signaling pathway / cytoplasmic sequestering of protein / tubulin deacetylation / actin crosslink formation / blood coagulation, intrinsic pathway / protein localization to bicellular tight junction / OAS antiviral response / positive regulation of actin filament bundle assembly / positive regulation of neuron migration / positive regulation of potassium ion transmembrane transport / Cell-extracellular matrix interactions / early endosome to late endosome transport / apical dendrite / Fc-gamma receptor I complex binding / cell-cell junction organization / positive regulation of neural precursor cell proliferation / positive regulation of platelet activation / protein localization to cell surface / wound healing, spreading of cells / negative regulation of transcription by RNA polymerase I / megakaryocyte development / GP1b-IX-V activation signalling / cortical cytoskeleton / positive regulation of axon regeneration / receptor clustering / SMAD binding / RHO GTPases activate PAKs / actin filament bundle / brush border / semaphorin-plexin signaling pathway / mitotic spindle assembly / cilium assembly / potassium channel regulator activity / epithelial to mesenchymal transition / blood vessel remodeling / axonal growth cone / heart morphogenesis / positive regulation of substrate adhesion-dependent cell spreading / release of sequestered calcium ion into cytosol / regulation of cell migration / dendritic shaft / protein localization to plasma membrane / G protein-coupled receptor binding / actin filament / protein kinase C binding / synapse organization / mRNA transcription by RNA polymerase II / establishment of protein localization / trans-Golgi network / negative regulation of protein catabolic process / negative regulation of DNA-binding transcription factor activity / cerebral cortex development / kinase binding / small GTPase binding / platelet aggregation / Z disc / positive regulation of protein import into nucleus / cell-cell junction / actin filament binding / actin cytoskeleton / Platelet degranulation / GTPase binding / negative regulation of neuron projection development / actin cytoskeleton organization / postsynapse / perikaryon / angiogenesis / DNA-binding transcription factor binding / positive regulation of canonical NF-kappaB signal transduction / transmembrane transporter binding / protein stabilization / cadherin binding / focal adhesion / glutamatergic synapse / nucleolus / negative regulation of apoptotic process / perinuclear region of cytoplasm / protein homodimerization activity / RNA binding / extracellular exosome / extracellular region / membrane / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Filamin family / Filamin/ABP280 repeat / Filamin-type immunoglobulin domains / Filamin/ABP280 repeat / Filamin/ABP280 repeat profile. / Filamin/ABP280 repeat-like / Actinin-type actin-binding domain signature 1. / Actinin-type actin-binding domain signature 2. / Actinin-type actin-binding domain, conserved site / Calponin homology domain ...Filamin family / Filamin/ABP280 repeat / Filamin-type immunoglobulin domains / Filamin/ABP280 repeat / Filamin/ABP280 repeat profile. / Filamin/ABP280 repeat-like / Actinin-type actin-binding domain signature 1. / Actinin-type actin-binding domain signature 2. / Actinin-type actin-binding domain, conserved site / Calponin homology domain / Calponin homology (CH) domain / Calponin homology domain / CH domain superfamily / Calponin homology (CH) domain profile. / Immunoglobulin E-set / Immunoglobulins / Immunoglobulin-like fold / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3070081803 Å
AuthorsHaataja, T.J.K. / Pentikainen, U.
Funding support Finland, 1items
OrganizationGrant numberCountry
Academy of Finland283481 Finland
CitationJournal: Structure / Year: 2019
Title: Non-syndromic Mitral Valve Dysplasia Mutation Changes the Force Resilience and Interaction of Human Filamin A.
Authors: Tatu J K Haataja / Rafael C Bernardi / Simon Lecointe / Romain Capoulade / Jean Merot / Ulla Pentikäinen /
Abstract: Filamin A (FLNa), expressed in endocardial endothelia during fetal valve morphogenesis, is key in cardiac development. Missense mutations in FLNa cause non-syndromic mitral valve dysplasia (FLNA-MVD). ...Filamin A (FLNa), expressed in endocardial endothelia during fetal valve morphogenesis, is key in cardiac development. Missense mutations in FLNa cause non-syndromic mitral valve dysplasia (FLNA-MVD). Here, we aimed to reveal the currently unknown underlying molecular mechanism behind FLNA-MVD caused by the FLNa P637Q mutation. The solved crystal structure of the FLNa3-5 P637Q revealed that this mutation causes only minor structural changes close to mutation site. These changes were observed to significantly affect FLNa's ability to transmit cellular force and to interact with its binding partner. The performed steered molecular dynamics simulations showed that significantly lower forces are needed to split domains 4 and 5 in FLNA-MVD than with wild-type FLNa. The P637Q mutation was also observed to interfere with FLNa's interactions with the protein tyrosine phosphatase PTPN12. Our results provide a crucial step toward understanding the molecular bases behind FLNA-MVD, which is critical for the development of drug-based therapeutics.
History
DepositionNov 3, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 16, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Jan 17, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Filamin-A


Theoretical massNumber of molelcules
Total (without water)31,0501
Polymers31,0501
Non-polymers00
Water95553
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: SAXS, The ab initio model of the protein is in good agreement with the obtained crystal structure
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.721, 60.721, 163.178
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65
Space group name HallP65
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: -x,-y,z+1/2

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Components

#1: Protein Filamin-A / FLN-A / Actin-binding protein 280 / ABP-280 / Alpha-filamin / Endothelial actin-binding protein / ...FLN-A / Actin-binding protein 280 / ABP-280 / Alpha-filamin / Endothelial actin-binding protein / Filamin-1 / Non-muscle filamin


Mass: 31049.963 Da / Num. of mol.: 1 / Mutation: P637Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLNA, FLN, FLN1 / Production host: Escherichia coli (E. coli) / References: UniProt: P21333
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 2.81 Å3/Da / Density % sol: 56.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.05 M ammonium citrate, 18 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.961 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Feb 6, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.961 Å / Relative weight: 1
ReflectionResolution: 2.3→37.81 Å / Num. obs: 14953 / % possible obs: 100 % / Redundancy: 11.9 % / Biso Wilson estimate: 45.43 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.038 / Rpim(I) all: 0.011 / Rrim(I) all: 0.04 / Net I/σ(I): 36.96
Reflection shellResolution: 2.31→2.43 Å / Rmerge(I) obs: 0.295 / Mean I/σ(I) obs: 8.3 / Num. measured obs: 26398 / Num. unique all: 2188 / CC1/2: 0.979 / Rpim(I) all: 0.088 / Rrim(I) all: 0.308 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIXdev_2313-000refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4M9P

4m9p


Resolution: 2.3070081803→37.8064654662 Å / SU ML: 0.349809960694 / Cross valid method: FREE R-VALUE / σ(F): 1.40559062127 / Phase error: 30.1292298193
RfactorNum. reflection% reflection
Rfree0.273389216854 762 5.0963081862 %
Rwork0.244538815652 --
obs0.245907158772 14952 99.7930988454 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 71.13 Å2
Refinement stepCycle: LAST / Resolution: 2.3070081803→37.8064654662 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2165 0 0 53 2218
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003113118092682213
X-RAY DIFFRACTIONf_angle_d0.6372366846312995
X-RAY DIFFRACTIONf_chiral_restr0.0502412202773315
X-RAY DIFFRACTIONf_plane_restr0.0050270533558402
X-RAY DIFFRACTIONf_dihedral_angle_d15.82764962471320
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.307-2.48510.3561179219571860.3266597668372788X-RAY DIFFRACTION99.2656875834
2.4851-2.73510.363834884061330.326848393822856X-RAY DIFFRACTION100
2.7351-3.13070.322093646421740.3004666121292813X-RAY DIFFRACTION99.9665327979
3.1307-3.94370.2659800487831200.241026232932863X-RAY DIFFRACTION99.8326639893
3.9437-37.81150.2209907686291490.1976310559372870X-RAY DIFFRACTION99.9007279947
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)
15.0707712202-3.582234237343.68500388485.64684532097-4.673726619348.04529940341-0.05350912239190.568431694345-0.02245988126840.118714317912-0.1247304457930.0596084083591-1.168793195280.652780244930.01435455434560.438828666236-0.0803905316633-0.01853470506830.269802146661-0.01571285992520.351903307836128.38123521761.3862678497-14.1737945416
21.605950322360.2701961267252.99775416270.261001138209-0.2319488300969.24891401908-0.639952793096-0.3708945491490.3392480996220.6307869465050.247071644965-0.230327587031-1.35674025776-0.447758281080.3809412184580.6613602438580.0474117753489-0.07964409347070.265532063167-0.0137949165090.447332950198129.71905848560.2543678427-4.18471754055
38.681613220313.73610337159-2.250322532265.257017358282.130992016376.0612362588-0.227253288052-0.4849980588360.446541912359-0.002010158253070.01047137401630.4095616149810.95645877587-0.1387477944530.2402509424960.641302056008-0.0991501183259-0.08782844537920.286292322804-0.03047906369450.434126931357128.54489784945.2700690876.13910984081
49.183709454622.44306719543-2.237046854473.56287641796-0.3767037644735.06344775162-0.628916136794-0.1678874737880.574151317333-0.3715714416340.4540136611420.05849796887650.610670561405-0.4744685585290.1567195343850.763038403963-0.149587204339-0.2082305628030.2980588276460.08847390968660.505560446054128.83070622447.47200253163.0484133114
51.47545320774-0.172791944554-0.9402493290876.715567265830.9364033366390.7033624821430.01202459645290.388111749603-1.76531166921-0.931185286698-0.2780423319912.283086462261.70892772451-0.58300784158-1.498178153761.91490218541-0.6873813544740.2975203102930.764349779552-0.3984025818321.08489175792124.00621537727.877271163-7.25426018146
65.43145547522-2.41527564623-4.025092174215.41787887346-0.7785639951766.27714604098-1.98052165542-0.379643519567-1.263118262970.6363614681480.618690850419-0.1996365956033.16112491462-0.08063867353540.05437519821262.016845997190.07623718899970.5121596571120.5200064321390.01278389099460.822627381674139.14633009924.7399427795-4.09725052354
76.17505080799-1.40104750262-4.748361661013.038354869391.61093040976.82185373072-1.07438658828-0.0764523391627-0.9844429057631.099641937980.427184930399-0.0669947048012.602911441250.5369663199750.4893945100231.327055176070.1429011678470.2389657923840.455565726875-0.04236476286440.516342067732140.53217573731.9360506432-2.99901492975
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 476 through 547 )
2X-RAY DIFFRACTION2chain 'A' and (resid 548 through 586 )
3X-RAY DIFFRACTION3chain 'A' and (resid 587 through 624 )
4X-RAY DIFFRACTION4chain 'A' and (resid 625 through 664 )
5X-RAY DIFFRACTION5chain 'A' and (resid 665 through 679 )
6X-RAY DIFFRACTION6chain 'A' and (resid 680 through 706 )
7X-RAY DIFFRACTION7chain 'A' and (resid 707 through 763 )

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