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- EMDB-27158: VWF tubule derived from dimeric D1-A2 -

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Basic information

Entry
Database: EMDB / ID: EMD-27158
TitleVWF tubule derived from dimeric D1-A2
Map dataMap output from Relion refinement (half maps included) autosharpened in Phenix.
Sample
  • Complex: Von Willebrand Factor tubule derived from dimeric D1-A2
    • Protein or peptide: Von Willebrand Factor (D1-A2)
KeywordsVWF / tubule / Blood clotting
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 4.7 Å
AuthorsAnderson JR / Li J / Springer TA / Brown A
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)1F30HL162128 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01-HL148755 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01-GM141109 United States
CitationJournal: Blood / Year: 2022
Title: Structures of VWF tubules before and after concatemerization reveal a mechanism of disulfide bond exchange.
Authors: Jacob R Anderson / Jing Li / Timothy A Springer / Alan Brown /
Abstract: von Willebrand factor (VWF) is an adhesive glycoprotein that circulates in the blood as disulfide-linked concatemers and functions in primary hemostasis. The loss of long VWF concatemers is ...von Willebrand factor (VWF) is an adhesive glycoprotein that circulates in the blood as disulfide-linked concatemers and functions in primary hemostasis. The loss of long VWF concatemers is associated with the excessive bleeding of type 2A von Willebrand disease (VWD). Formation of the disulfide bonds that concatemerize VWF requires VWF to self-associate into helical tubules, yet how the helical tubules template intermolecular disulfide bonds is not known. Here, we report electron cryomicroscopy (cryo-EM) structures of VWF tubules before and after intermolecular disulfide bond formation. The structures provide evidence that VWF tubulates through a charge-neutralization mechanism and that the A1 domain enhances tubule length by crosslinking successive helical turns. In addition, the structures reveal disulfide states before and after disulfide bond-mediated concatemerization. The structures and proposed assembly mechanism provide a foundation to rationalize VWD-causing mutations.
History
DepositionJun 1, 2022-
Header (metadata) releaseJul 6, 2022-
Map releaseJul 6, 2022-
UpdateJan 17, 2024-
Current statusJan 17, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27158.png

Downloads & links

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Map

FileDownload / File: emd_27158.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap output from Relion refinement (half maps included) autosharpened in Phenix.
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 3.22
Minimum - Maximum-6.3632874 - 13.889120999999999
Average (Standard dev.)-0.00000000000451 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 422.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27158_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: 2 of 2 half maps of D1-A2 VWF

Fileemd_27158_half_map_1.map
Annotation2 of 2 half maps of D1-A2 VWF
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: 1 of 2 half maps of D1-A2 VWF

Fileemd_27158_half_map_2.map
Annotation1 of 2 half maps of D1-A2 VWF
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Von Willebrand Factor tubule derived from dimeric D1-A2

EntireName: Von Willebrand Factor tubule derived from dimeric D1-A2
Components
  • Complex: Von Willebrand Factor tubule derived from dimeric D1-A2
    • Protein or peptide: Von Willebrand Factor (D1-A2)

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Supramolecule #1: Von Willebrand Factor tubule derived from dimeric D1-A2

SupramoleculeName: Von Willebrand Factor tubule derived from dimeric D1-A2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.0 kDa/nm

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Macromolecule #1: Von Willebrand Factor (D1-A2)

MacromoleculeName: Von Willebrand Factor (D1-A2) / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MIPARFAGVL LALALILPGT LCAEGTRGRS STARCSLFGS DFVNTFDGSM YSFAGYCSYL LAGGCQKRSF SIIGDFQNGK RVSLSVYLGE FFDIHLFVNG TVTQGDQRVS MPYASKGLYL ETEAGYYKLS GEAYGFVARI DGSGNFQVLL SDRYFNKTCG LCGNFNIFAE ...String:
MIPARFAGVL LALALILPGT LCAEGTRGRS STARCSLFGS DFVNTFDGSM YSFAGYCSYL LAGGCQKRSF SIIGDFQNGK RVSLSVYLGE FFDIHLFVNG TVTQGDQRVS MPYASKGLYL ETEAGYYKLS GEAYGFVARI DGSGNFQVLL SDRYFNKTCG LCGNFNIFAE DDFMTQEGTL TSDPYDFANS WALSSGEQWC ERASPPSSSC NISSGEMQKG LWEQCQLLKS TSVFARCHPL VDPEPFVALC EKTLCECAGG LECACPALLE YARTCAQEGM VLYGWTDHSA CSPVCPAGME YRQCVSPCAR TCQSLHINEM CQERCVDGCS CPEGQLLDEG LCVESTECPC VHSGKRYPPG TSLSRDCNTC ICRNSQWICS NEECPGECLV TGQSHFKSFD NRYFTFSGIC QYLLARDCQD HSFSIVIETV QCADDRDAVC TRSVTVRLPG LHNSLVKLKH GAGVAMDGQD VQLPLLKGDL RIQHTVTASV RLSYGEDLQM DWDGRGRLLV KLSPVYAGKT CGLCGNYNGN QGDDFLTPSG LAEPRVEDFG NAWKLHGDCQ DLQKQHSDPC ALNPRMTRFS EEACAVLTSP TFEACHRAVS PLPYLRNCRY DVCSCSDGRE CLCGALASYA AACAGRGVRV AWREPGRCEL NCPKGQVYLQ CGTPCNLTCR SLSYPDEECN EACLEGCFCP PGLYMDERGD CVPKAQCPCY YDGEIFQPED IFSDHHTMCY CEDGFMHCTM SGVPGSLLPD AVLSSPLSHA SASLSCRPPM VKLVCPADNL RAEGLECAKT CQNYDLECMS MGCVSGCLCP PGMVRHENRC VALERCPCFH QGKEYAPGET VKIGCNTCVC RDRKWNCTDH VCDATCSTIG MAHYLTFDGL KYLFPGECQY VLVQDYCGSN PGTFRILVGN KGCSHPSVKC KKRVTILVEG GEIELFDGEV NVKRPMKDET HFEVVESGRY IILLLGKALS VVWDRHLSIS VVLKQTYQEK VCGLCGNFDG IQNNDLTSSN LQVEEDPVDF GNSWKVSSQC ADTRKVPLDS SPATCHNNIM KQTMVDSSCR ILTSDVFQDC NKLVDPEPYL DVCIYDTCSC ESIGDCACFC DTIAAYAHVC AQHGKVVTWR TATLCPQSCE ERNLRENGYE CEWRYNSCAP ACQVTCQHPE PLACPVQCVE GCHAHCPPGK ILDELLQTCV DPEDCPVCEV AGRRFASGKK VTLNPSDPEH CQICHCDVVN LTCEACQEPG GLVVPPTDAP VSPTTLYVED ISEPPLHDFY CSRLLDLVFL LDGSSRLSEA EFEVLKAFVV DMMERLRISQ KWVRVAVVEY HDGSHAYIGL KDRKRPSELR RIASQVKYAG SQVASTSEVL KYTLFQIFSK IDRPEASRIA LLLMASQEPQ RMSRNFVRYV QGLKKKKVIV IPVGIGPHAN LKQIRLIEKQ APENKAFVLS SVDELEQQRD EIVSYLCDLA PEAPPPTLPP DMAQVTVGPG LLGVSTLGPK RNSMVLDVAF VLEGSDKIGE ADFNRSKEFM EEVIQRMDVG QDSIHVTVLQ YSYMVTVEYP FSEAQSKGDI LQRVREIRYQ GGNRTNTGLA LRYLSDHSFL VSQGDREQAP NLVYMVTGNP ASDEIKRLPG DIQVVPIGVG PNANVQELER IGWPNAPILI QDFETLPREA PDLVLQRCCS

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statehelical array

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Sample preparation

Concentration1 mg/mL
BufferpH: 5.2
Component:
ConcentrationFormulaName
100.0 mM(CH3)2AsO2NaSodium cacodylate
10.0 mMCaCl2Calcium Chloride
100.0 mMNaClSodium Chloride

Details: 100 mM Sodium Cacodylate at pH 5.2, 10 mM CaCl2, and 100 mM NaCl.
GridModel: Quantifoil R2/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TECNAI ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 27.0 Å
Applied symmetry - Helical parameters - Δ&Phi: 83.3 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 4.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4-beta) / Number images used: 78108
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6tm2

Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4-beta)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL

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