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- EMDB-19739: Full-length human cystathionine beta-synthase, basal state, parti... -

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Basic information

Entry
Database: EMDB / ID: EMD-19739
TitleFull-length human cystathionine beta-synthase, basal state, partially degraded tetramer
Map data
Sample
  • Complex: Helical assembly of full-length human cystathionine beta-synthase in the basal state
    • Protein or peptide: Cystathionine beta-synthaseCystathionine beta synthase
    • Protein or peptide: Cystathionine beta-synthaseCystathionine beta synthase
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
  • Ligand: PYRIDOXAL-5'-PHOSPHATEPyridoxal phosphate
KeywordsFilament / Allostery / TRANSFERASE
Function / homology
Function and homology information


Cysteine formation from homocysteine / homocysteine catabolic process / modified amino acid binding / cystathionine beta-synthase / cystathionine beta-synthase activity / cysteine biosynthetic process via cystathionine / Metabolism of ingested SeMet, Sec, MeSec into H2Se / homocysteine metabolic process / L-serine catabolic process / carbon monoxide binding ...Cysteine formation from homocysteine / homocysteine catabolic process / modified amino acid binding / cystathionine beta-synthase / cystathionine beta-synthase activity / cysteine biosynthetic process via cystathionine / Metabolism of ingested SeMet, Sec, MeSec into H2Se / homocysteine metabolic process / L-serine catabolic process / carbon monoxide binding / hydrogen sulfide biosynthetic process / cartilage development involved in endochondral bone morphogenesis / L-serine metabolic process / regulation of nitric oxide mediated signal transduction / L-cysteine catabolic process / cysteine biosynthetic process / cerebellum morphogenesis / nitric oxide binding / cysteine biosynthetic process from serine / DNA protection / endochondral ossification / transsulfuration / S-adenosyl-L-methionine binding / response to folic acid / nitrite reductase (NO-forming) activity / superoxide metabolic process / maternal process involved in female pregnancy / blood vessel remodeling / blood vessel diameter maintenance / oxygen binding / pyridoxal phosphate binding / cellular response to hypoxia / ubiquitin protein ligase binding / heme binding / negative regulation of apoptotic process / enzyme binding / protein homodimerization activity / identical protein binding / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Cystathionine beta-synthase, C-terminal domain / Cystathionine beta-synthase / Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site / Cysteine synthase/cystathionine beta-synthase P-phosphate attachment site. / CBS domain superfamily / Domain in cystathionine beta-synthase and other proteins. / Pyridoxal-phosphate dependent enzyme / Tryptophan synthase beta subunit-like PLP-dependent enzyme / Pyridoxal-phosphate dependent enzyme / CBS domain ...Cystathionine beta-synthase, C-terminal domain / Cystathionine beta-synthase / Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site / Cysteine synthase/cystathionine beta-synthase P-phosphate attachment site. / CBS domain superfamily / Domain in cystathionine beta-synthase and other proteins. / Pyridoxal-phosphate dependent enzyme / Tryptophan synthase beta subunit-like PLP-dependent enzyme / Pyridoxal-phosphate dependent enzyme / CBS domain / CBS domain / CBS domain profile.
Similarity search - Domain/homology
Cystathionine beta-synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsMcCorvie TJ / Yue WW
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
CitationJournal: Nat Commun / Year: 2024
Title: Architecture and regulation of filamentous human cystathionine beta-synthase.
Authors: Thomas J McCorvie / Douglas Adamoski / Raquel A C Machado / Jiazhi Tang / Henry J Bailey / Douglas S M Ferreira / Claire Strain-Damerell / Arnaud Baslé / Andre L B Ambrosio / Sandra M G Dias / Wyatt W Yue /
Abstract: Cystathionine beta-synthase (CBS) is an essential metabolic enzyme across all domains of life for the production of glutathione, cysteine, and hydrogen sulfide. Appended to the conserved catalytic ...Cystathionine beta-synthase (CBS) is an essential metabolic enzyme across all domains of life for the production of glutathione, cysteine, and hydrogen sulfide. Appended to the conserved catalytic domain of human CBS is a regulatory domain that modulates activity by S-adenosyl-L-methionine (SAM) and promotes oligomerisation. Here we show using cryo-electron microscopy that full-length human CBS in the basal and SAM-bound activated states polymerises as filaments mediated by a conserved regulatory domain loop. In the basal state, CBS regulatory domains sterically block the catalytic domain active site, resulting in a low-activity filament with three CBS dimers per turn. This steric block is removed when in the activated state, one SAM molecule binds to the regulatory domain, forming a high-activity filament with two CBS dimers per turn. These large conformational changes result in a central filament of SAM-stabilised regulatory domains at the core, decorated with highly flexible catalytic domains. Polymerisation stabilises CBS and reduces thermal denaturation. In PC-3 cells, we observed nutrient-responsive CBS filamentation that disassembles when methionine is depleted and reversed in the presence of SAM. Together our findings extend our understanding of CBS enzyme regulation, and open new avenues for investigating the pathogenic mechanism and therapeutic opportunities for CBS-associated disorders.
History
DepositionFeb 23, 2024-
Header (metadata) releaseApr 17, 2024-
Map releaseApr 17, 2024-
UpdateApr 17, 2024-
Current statusApr 17, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19739.png

Downloads & links

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Map

FileDownload / File: emd_19739.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 500 pix.
= 467. Å		0.93 Å/pix.
x 500 pix.
= 467. Å		0.93 Å/pix.
x 500 pix.
= 467. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.934 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.4158435 - 0.72304046
Average (Standard dev.)-0.00019473815 (±0.012238338)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions500500500
Spacing500500500
CellA=B=C: 467.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19739_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: non-sharpened map

Fileemd_19739_additional_1.map
Annotationnon-sharpened map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_19739_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_19739_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Helical assembly of full-length human cystathionine beta-synthase...

EntireName: Helical assembly of full-length human cystathionine beta-synthase in the basal state
Components
  • Complex: Helical assembly of full-length human cystathionine beta-synthase in the basal state
    • Protein or peptide: Cystathionine beta-synthaseCystathionine beta synthase
    • Protein or peptide: Cystathionine beta-synthaseCystathionine beta synthase
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
  • Ligand: PYRIDOXAL-5'-PHOSPHATEPyridoxal phosphate

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Supramolecule #1: Helical assembly of full-length human cystathionine beta-synthase...

SupramoleculeName: Helical assembly of full-length human cystathionine beta-synthase in the basal state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cystathionine beta-synthase

MacromoleculeName: Cystathionine beta-synthase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: cystathionine beta-synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.980578 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SMPSETPQAE VGPTGCPHRS GPHSAKGSLE KGSPEDKEAK EPLWIRPDAP SRCTWQLGRP ASESPHHHTA PAKSPKILPD ILKKIGDTP MVRINKIGKK FGLKCELLAK CEFFNAGGSV (LLP)DRISLRMIE DAERDGTLKP GDTIIEPTSG NTGIGLA LA AAVRGYRCII ...String:
SMPSETPQAE VGPTGCPHRS GPHSAKGSLE KGSPEDKEAK EPLWIRPDAP SRCTWQLGRP ASESPHHHTA PAKSPKILPD ILKKIGDTP MVRINKIGKK FGLKCELLAK CEFFNAGGSV (LLP)DRISLRMIE DAERDGTLKP GDTIIEPTSG NTGIGLA LA AAVRGYRCII VMPEKMSSEK VDVLRALGAE IVRTPTNARF DSPESHVGVA WRLKNEIPNS HILDQYRNAS NPLAHYDT T ADEILQQCDG KLDMLVASVG TGGTITGIAR KLKEKCPGCR IIGVDPEGSI LAEPEELNQT EQTTYEVEGI GYDFIPTVL DRTVVDKWFK SNDEEAFTFA RMLIAQEGLL CGGSAGSTVA VAVKAAQELQ EGQRCVVILP DSVRNYMTKF LSDRWMLQKG FLKEEDLTE KKPWWWHLRV QELGLSAPLT VLPTITCGHT IEILREKGFD QAPVVDEAGV ILGMVTLGNM LSSLLAGKVQ P SDQVGKVI YKQFKQIRLT DTLGRLSHIL EMDHFALVVH EQIQYHSTGK SSQRQMVFGV VTAIDLLNFV AAQERDQK

UniProtKB: Cystathionine beta-synthase

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Macromolecule #2: Cystathionine beta-synthase

MacromoleculeName: Cystathionine beta-synthase / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: cystathionine beta-synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.752453 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SMPSETPQAE VGPTGCPHRS GPHSAKGSLE KGSPEDKEAK EPLWIRPDAP SRCTWQLGRP ASESPHHHTA PAKSPKILPD ILKKIGDTP MVRINKIGKK FGLKCELLAK CEFFNAGGSV KDRISLRMIE DAERDGTLKP GDTIIEPTSG NTGIGLALAA A VRGYRCII ...String:
SMPSETPQAE VGPTGCPHRS GPHSAKGSLE KGSPEDKEAK EPLWIRPDAP SRCTWQLGRP ASESPHHHTA PAKSPKILPD ILKKIGDTP MVRINKIGKK FGLKCELLAK CEFFNAGGSV KDRISLRMIE DAERDGTLKP GDTIIEPTSG NTGIGLALAA A VRGYRCII VMPEKMSSEK VDVLRALGAE IVRTPTNARF DSPESHVGVA WRLKNEIPNS HILDQYRNAS NPLAHYDTTA DE ILQQCDG KLDMLVASVG TGGTITGIAR KLKEKCPGCR IIGVDPEGSI LAEPEELNQT EQTTYEVEGI GYDFIPTVLD RTV VDKWFK SNDEEAFTFA RMLIAQEGLL CGGSAGSTVA VAVKAAQELQ EGQRCVVILP DSVRNYMTKF LSDRWMLQKG FLKE EDLTE KKPWWWHLRV QELGLSAPLT VLPTITCGHT IEILREKGFD QAPVVDEAGV ILGMVTLGNM LSSLLAGKVQ PSDQV GKVI YKQFKQIRLT DTLGRLSHIL EMDHFALVVH EQIQYHSTGK SSQRQMVFGV VTAIDLLNFV AAQERDQK

UniProtKB: Cystathionine beta-synthase

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Macromolecule #3: PROTOPORPHYRIN IX CONTAINING FE

MacromoleculeName: PROTOPORPHYRIN IX CONTAINING FE / type: ligand / ID: 3 / Number of copies: 4 / Formula: HEM
Molecular weightTheoretical: 616.487 Da
Chemical component information

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE / Heme B

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Macromolecule #4: PYRIDOXAL-5'-PHOSPHATE

MacromoleculeName: PYRIDOXAL-5'-PHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: PLP
Molecular weightTheoretical: 247.142 Da
Chemical component information

ChemComp-PLP:
PYRIDOXAL-5'-PHOSPHATE / Pyridoxal phosphate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

Concentration1.0 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
25.0 mMHEPES
200.0 mMsodium chlorideNaClSodium chloride
2.0 mMTCEP
0.005 % (v/v)Tween-20

Details: filter sterile 25 mM HEPES, pH 7.5, 200 mM NaCl, 2.0 mM TCEP, 0.005% (v/v) tween-20
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / 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

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.4000000000000001 µm / Nominal magnification: 150000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 2628 / Average exposure time: 5.18 sec. / Average electron dose: 50.0 e/Å2

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Image processing

Particle selectionNumber selected: 1190611
Startup modelType of model: OTHER / Details: ab-inito from data
Initial angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC (ver. 3.3.2)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 3.3.2)
Final angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC (ver. 3.3.2)
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.2) / Number images used: 67901
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

4coo


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 64.75
Output model

PDB-8s5l:
Full-length human cystathionine beta-synthase, basal state, partially degraded tetramer

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