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- EMDB-12747: (h-alpha2M)4 native I -

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Basic information

Entry
Database: EMDB / ID: EMD-12747
Title(h-alpha2M)4 native I
Map data(ha2M)4 native I
Sample
  • Complex: Human alpha-2-macroglobulin native I
    • Protein or peptide: Alpha-2-macroglobulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsalpha2-macroglobulin / proteinase / serum proteostasis / hydrolase inhibitor / PROTEIN BINDING
Function / homology
Function and homology information


negative regulation of complement activation, lectin pathway / interleukin-1 binding / interleukin-8 binding / tumor necrosis factor binding / HDL assembly / endopeptidase inhibitor activity / growth factor binding / Intrinsic Pathway of Fibrin Clot Formation / Degradation of the extracellular matrix / platelet alpha granule lumen ...negative regulation of complement activation, lectin pathway / interleukin-1 binding / interleukin-8 binding / tumor necrosis factor binding / HDL assembly / endopeptidase inhibitor activity / growth factor binding / Intrinsic Pathway of Fibrin Clot Formation / Degradation of the extracellular matrix / platelet alpha granule lumen / stem cell differentiation / serine-type endopeptidase inhibitor activity / calcium-dependent protein binding / Platelet degranulation / : / protease binding / blood microparticle / signaling receptor binding / enzyme binding / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
Alpha-2-macroglobulin, TED domain / TonB box, conserved site / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Macroglobulin domain MG4 / Macroglobulin domain MG4 / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily ...Alpha-2-macroglobulin, TED domain / TonB box, conserved site / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Macroglobulin domain MG4 / Macroglobulin domain MG4 / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Alpha-2-macroglobulin / Macroglobulin domain / Alpha-2-macroglobulin, bait region domain / Alpha-macroglobulin-like, TED domain / Alpha-2-macroglobulin family / MG2 domain / A-macroglobulin TED domain / Alpha-2-macroglobulin bait region domain / Alpha-2-Macroglobulin / Alpha-2-macroglobulin family / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Immunoglobulin E-set / Immunoglobulin-like fold
Similarity search - Domain/homology
Alpha-2-macroglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsLuque D / Goulas T
Funding support Spain, 4 items
OrganizationGrant numberCountry
Spanish Ministry of Economy and CompetitivenessBFU2017-88736-R Spain
Spanish Ministry of Economy and CompetitivenessBFU2019-107725-RB-I00 Spain
Spanish Ministry of Economy and CompetitivenessJCI-2012-13573 Spain
Spanish Ministry of Science, Innovation, and UniversitiesBES2016-076877 Spain
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α-macroglobulin.
Authors: Daniel Luque / Theodoros Goulas / Carlos P Mata / Soraia R Mendes / F Xavier Gomis-Rüth / José R Castón /
Abstract: Human α2-macroglobulin (hα2M) is a multidomain protein with a plethora of essential functions, including transport of signaling molecules and endopeptidase inhibition in innate immunity. Here, we ...Human α2-macroglobulin (hα2M) is a multidomain protein with a plethora of essential functions, including transport of signaling molecules and endopeptidase inhibition in innate immunity. Here, we dissected the molecular mechanism of the inhibitory function of the ∼720-kDa hα2M tetramer through eight cryo–electron microscopy (cryo-EM) structures of complexes from human plasma. In the native complex, the hα2M subunits are organized in two flexible modules in expanded conformation, which enclose a highly porous cavity in which the proteolytic activity of circulating plasma proteins is tested. Cleavage of bait regions exposed inside the cavity triggers rearrangement to a compact conformation, which closes openings and entraps the prey proteinase. After the expanded-to-compact transition, which occurs independently in the four subunits, the reactive thioester bond triggers covalent linking of the proteinase, and the receptor-binding domain is exposed on the tetramer surface for receptor-mediated clearance from circulation. These results depict the molecular mechanism of a unique suicidal inhibitory trap.
History
DepositionApr 13, 2021-
Header (metadata) releaseApr 20, 2022-
Map releaseApr 20, 2022-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_12747.png

Downloads & links

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Map

FileDownload / File: emd_12747.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation(ha2M)4 native I
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 320 pix.
= 335.04 Å		1.05 Å/pix.
x 320 pix.
= 335.04 Å		1.05 Å/pix.
x 320 pix.
= 335.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.047 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.0021409825 - 0.107277215
Average (Standard dev.)0.0001174966 (±0.0029370394)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-160-160-160
Dimensions320320320
Spacing320320320
CellA=B=C: 335.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Human alpha-2-macroglobulin native I

EntireName: Human alpha-2-macroglobulin native I
Components
  • Complex: Human alpha-2-macroglobulin native I
    • Protein or peptide: Alpha-2-macroglobulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human alpha-2-macroglobulin native I

SupramoleculeName: Human alpha-2-macroglobulin native I / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human) / Organ: Blood plasma
Molecular weightTheoretical: 700 KDa

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Macromolecule #1: Alpha-2-macroglobulin

MacromoleculeName: Alpha-2-macroglobulin / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 163.465062 KDa
SequenceString: MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV SASLESVRGN RSLFTDLEAE NDVLHCVAF AVPKSSSNEE VMFLTVQVKG PTQEFKKRTT VMVKNEDSLV FVQTDKSIYK PGQTVKFRVV SMDENFHPLN E LIPLVYIQ ...String:
MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV SASLESVRGN RSLFTDLEAE NDVLHCVAF AVPKSSSNEE VMFLTVQVKG PTQEFKKRTT VMVKNEDSLV FVQTDKSIYK PGQTVKFRVV SMDENFHPLN E LIPLVYIQ DPKGNRIAQW QSFQLEGGLK QFSFPLSSEP FQGSYKVVVQ KKSGGRTEHP FTVEEFVLPK FEVQVTVPKI IT ILEEEMN VSVCGLYTYG KPVPGHVTVS ICRKYSDASD CHGEDSQAFC EKFSGQLNSH GCFYQQVKTK VFQLKRKEYE MKL HTEAQI QEEGTVVELT GRQSSEITRT ITKLSFVKVD SHFRQGIPFF GQVRLVDGKG VPIPNKVIFI RGNEANYYSN ATTD EHGLV QFSINTTNVM GTSLTVRVNY KDRSPCYGYQ WVSEEHEEAH HTAYLVFSPS KSFVHLEPMS HELPCGHTQT VQAHY ILNG GTLLGLKKLS FYYLIMAKGG IVRTGTHGLL VKQEDMKGHF SISIPVKSDI APVARLLIYA VLPTGDVIGD SAKYDV ENC LANKVDLSFS PSQSLPASHA HLRVTAAPQS VCALRAVDQS VLLMKPDAEL SASSVYNLLP EKDLTGFPGP LNDQDNE DC INRHNVYING ITYTPVSSTN EKDMYSFLED MGLKAFTNSK IRKPKMCPQL QQYEMHGPEG LRVGFYESDV MGRGHARL V HVEEPHTETV RKYFPETWIW DLVVVNSAGV AEVGVTVPDT ITEWKAGAFC LSEDAGLGIS STASLRAFQP FFVELTMPY SVIRGEAFTL KATVLNYLPK CIRVSVQLEA SPAFLAVPVE KEQAPHCICA NGRQTVSWAV TPKSLGNVNF TVSAEALESQ ELCGTEVPS VPEHGRKDTV IKPLLVEPEG LEKETTFNSL LCPSGGEVSE ELSLKLPPNV VEESARASVS VLGDILGSAM Q NTQNLLQM PYGCGEQNMV LFAPNIYVLD YLNETQQLTP EIKSKAIGYL NTGYQRQLNY KHYDGSYSTF GERYGRNQGN TW LTAFVLK TFAQARAYIF IDEAHITQAL IWLSQRQKDN GCFRSSGSLL NNAIKGGVED EVTLSAYITI ALLEIPLTVT HPV VRNALF CLESAWKTAQ EGDHGSHVYT KALLAYAFAL AGNQDKRKEV LKSLNEEAVK KDNSVHWERP QKPKAPVGHF YEPQ APSAE VEMTSYVLLA YLTAQPAPTS EDLTSATNIV KWITKQQNAQ GGFSSTQDTV VALHALSKYG AATFTRTGKA AQVTI QSSG TFSSKFQVDN NNRLLLQQVS LPELPGEYSM KVTGEGCVYL QTSLKYNILP EKEEFPFALG VQTLPQTCDE PKAHTS FQI SLSVSYTGSR SASNMAIVDV KMVSGFIPLK PTVKMLERSN HVSRTEVSSN HVLIYLDKVS NQTLSLFFTV LQDVPVR DL KPAIVKVYDY YETDEFAIAE YNAPCSKDLG NA

UniProtKB: Alpha-2-macroglobulin

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 26 / 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
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.1 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R2/2 / Material: COPPER/RHODIUM / Mesh: 300
VitrificationCryogen name: ETHANE / Instrument: LEICA EM CPC

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 12143 / Average electron dose: 39.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.25 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 47775
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1625000
Startup modelType of model: OTHER
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.1) / Number images used: 45669
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.1)
Final 3D classificationSoftware - Name: RELION (ver. 2.1)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER
Output model

PDB-7o7l:
(h-alpha2M)4 native I

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