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- EMDB-27157: VWF tubule derived from dimeric D1-A1 -

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Basic information

Entry
Database: EMDB / ID: EMD-27157
TitleVWF tubule derived from dimeric D1-A1
Map dataSingle central bead, autosharpened in phenix, stitched into repeating unit of tubule.
Sample
  • Complex: Von Willebrand Factor tubule derived from dimeric D1-A1
    • Protein or peptide: von Willebrand factor
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


Defective VWF binding to collagen type I / Enhanced cleavage of VWF variant by ADAMTS13 / Defective VWF cleavage by ADAMTS13 variant / Weibel-Palade body / Defective F8 binding to von Willebrand factor / Enhanced binding of GP1BA variant to VWF multimer:collagen / Defective binding of VWF variant to GPIb:IX:V / hemostasis / platelet alpha granule / Platelet Adhesion to exposed collagen ...Defective VWF binding to collagen type I / Enhanced cleavage of VWF variant by ADAMTS13 / Defective VWF cleavage by ADAMTS13 variant / Weibel-Palade body / Defective F8 binding to von Willebrand factor / Enhanced binding of GP1BA variant to VWF multimer:collagen / Defective binding of VWF variant to GPIb:IX:V / hemostasis / platelet alpha granule / Platelet Adhesion to exposed collagen / positive regulation of intracellular signal transduction / GP1b-IX-V activation signalling / p130Cas linkage to MAPK signaling for integrins / cell-substrate adhesion / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / immunoglobulin binding / GRB2:SOS provides linkage to MAPK signaling for Integrins / Integrin cell surface interactions / collagen binding / Intrinsic Pathway of Fibrin Clot Formation / Integrin signaling / extracellular matrix / platelet alpha granule lumen / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / platelet activation / response to wounding / 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 / Signaling by BRAF and RAF1 fusions / blood coagulation / integrin binding / Platelet degranulation / protein-folding chaperone binding / collagen-containing extracellular matrix / protease binding / cell adhesion / endoplasmic reticulum / extracellular space / extracellular exosome / extracellular region / identical protein binding
Similarity search - Function
von Willebrand factor, VWA N-terminal domain / Von Willebrand factor / VWA N-terminal / C8 domain / Uncharacterised domain, cysteine-rich / C8 / von Willebrand factor, type D domain / von Willebrand factor type D domain / VWFD domain profile. / von Willebrand factor (vWF) type D domain ...von Willebrand factor, VWA N-terminal domain / Von Willebrand factor / VWA N-terminal / C8 domain / Uncharacterised domain, cysteine-rich / C8 / von Willebrand factor, type D domain / von Willebrand factor type D domain / VWFD domain profile. / von Willebrand factor (vWF) type D domain / C-terminal cystine knot signature. / von Willebrand factor (vWF) type C domain / Trypsin Inhibitor-like, cysteine rich domain / Serine protease inhibitor-like superfamily / Trypsin Inhibitor like cysteine rich domain / C-terminal cystine knot domain profile. / Cystine knot, C-terminal / C-terminal cystine knot-like domain (CTCK) / von Willebrand factor type C domain / VWFC domain signature. / VWFC domain profile. / von Willebrand factor (vWF) type C domain / VWFC domain / von Willebrand factor type A domain / von Willebrand factor (vWF) type A domain / VWFA domain profile. / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily
Similarity search - Domain/homology
von Willebrand factor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.2 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-
UpdateOct 5, 2022-
Current statusOct 5, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27157.png

Downloads & links

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Map

FileDownload / File: emd_27157.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSingle central bead, autosharpened in phenix, stitched into repeating unit of tubule.
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 3.31
Minimum - Maximum-0.32261932 - 34.0538
Average (Standard dev.)0.30245975 (±1.4247578)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 407.03998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27157_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: 1 of 2 Half-Map of D1A1 dimer composed VWF tubule.

Fileemd_27157_half_map_1.map
Annotation1 of 2 Half-Map of D1A1 dimer composed VWF tubule.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: 2 of 2 Half-Map of D1A1 dimer composed VWF tubule.

Fileemd_27157_half_map_2.map
Annotation2 of 2 Half-Map of D1A1 dimer composed VWF tubule.
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-A1

EntireName: Von Willebrand Factor tubule derived from dimeric D1-A1
Components
  • Complex: Von Willebrand Factor tubule derived from dimeric D1-A1
    • Protein or peptide: von Willebrand factor
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Von Willebrand Factor tubule derived from dimeric D1-A1

SupramoleculeName: Von Willebrand Factor tubule derived from dimeric D1-A1
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: Expi293
Molecular weightTheoretical: 12.4 kDa/nm

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Macromolecule #1: von Willebrand factor

MacromoleculeName: von Willebrand factor / type: protein_or_peptide / ID: 1 / Number of copies: 16 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 162.300984 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MIPARFAGVL LALALILPGT LCAEGTRGRS STARCSLFGS DFVNTFDGSM YSFAGYCSYL LAGGCQKRSF SIIGDFQNGK RVSLSVYLG EFFDIHLFVN GTVTQGDQRV SMPYASKGLY LETEAGYYKL SGEAYGFVAR IDGSGNFQVL LSDRYFNKTC G LCGNFNIF ...String:
MIPARFAGVL LALALILPGT LCAEGTRGRS STARCSLFGS DFVNTFDGSM YSFAGYCSYL LAGGCQKRSF SIIGDFQNGK RVSLSVYLG EFFDIHLFVN GTVTQGDQRV SMPYASKGLY LETEAGYYKL SGEAYGFVAR IDGSGNFQVL LSDRYFNKTC G LCGNFNIF AEDDFMTQEG TLTSDPYDFA NSWALSSGEQ WCERASPPSS SCNISSGEMQ KGLWEQCQLL KSTSVFARCH PL VDPEPFV ALCEKTLCEC AGGLECACPA LLEYARTCAQ EGMVLYGWTD HSACSPVCPA GMEYRQCVSP CARTCQSLHI NEM CQERCV DGCSCPEGQL LDEGLCVEST ECPCVHSGKR YPPGTSLSRD CNTCICRNSQ WICSNEECPG ECLVTGQSHF KSFD NRYFT FSGICQYLLA RDCQDHSFSI VIETVQCADD RDAVCTRSVT VRLPGLHNSL VKLKHGAGVA MDGQDVQLPL LKGDL RIQH TVTASVRLSY GEDLQMDWDG RGRLLVKLSP VYAGKTCGLC GNYNGNQGDD FLTPSGLAEP RVEDFGNAWK LHGDCQ DLQ KQHSDPCALN PRMTRFSEEA CAVLTSPTFE ACHRAVSPLP YLRNCRYDVC SCSDGRECLC GALASYAAAC AGRGVRV AW REPGRCELNC PKGQVYLQCG TPCNLTCRSL SYPDEECNEA CLEGCFCPPG LYMDERGDCV PKAQCPCYYD GEIFQPED I FSDHHTMCYC EDGFMHCTMS GVPGSLLPDA VLSSPLSHAS ASLSCRPPMV KLVCPADNLR AEGLECAKTC QNYDLECMS MGCVSGCLCP PGMVRHENRC VALERCPCFH QGKEYAPGET VKIGCNTCVC RDRKWNCTDH VCDATCSTIG MAHYLTFDGL KYLFPGECQ YVLVQDYCGS NPGTFRILVG NKGCSHPSVK CKKRVTILVE GGEIELFDGE VNVKRPMKDE THFEVVESGR Y IILLLGKA LSVVWDRHLS ISVVLKQTYQ EKVCGLCGNF DGIQNNDLTS SNLQVEEDPV DFGNSWKVSS QCADTRKVPL DS SPATCHN NIMKQTMVDS SCRILTSDVF QDCNKLVDPE PYLDVCIYDT CSCESIGDCA CFCDTIAAYA HVCAQHGKVV TWR TATLCP QSCEERNLRE NGYECEWRYN SCAPACQVTC QHPEPLACPV QCVEGCHAHC PPGKILDELL QTCVDPEDCP VCEV AGRRF ASGKKVTLNP SDPEHCQICH CDVVNLTCEA CQEPGGLVVP PTDAPVSPTT LYVEDISEPP LHDFYCSRLL DLVFL LDGS SRLSEAEFEV LKAFVVDMME RLRISQKWVR VAVVEYHDGS HAYIGLKDRK RPSELRRIAS QVKYAGSQVA STSEVL KYT LFQIFSKIDR PEASRIALLL MASQEPQRMS RNFVRYVQGL KKKKVIVIPV GIGPHANLKQ IRLIEKQAPE NKAFVLS SV DELEQQRDEI VSYLCDLAPE AHHHHHH

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Macromolecule #2: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 2 / Number of copies: 48 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 80 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration0.6 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: 2.0 nm / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 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
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 26.8 Å
Applied symmetry - Helical parameters - Δ&Phi: 83.3 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.3)
Details: Resolution of tubule is 3.3. Resolution of masked central bead 3.2.
Number images used: 250388
CTF correctionSoftware - Name: CTFFIND (ver. 4.1.14)
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6tm2

Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 3.1.3)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-8d3d:
VWF tubule derived from dimeric D1-A1

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