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- EMDB-13850: Structure of TEV cleaved A2ML1 dimer (A2ML1-TT dimer) -

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Basic information

Entry
Database: EMDB / ID: EMD-13850
TitleStructure of TEV cleaved A2ML1 dimer (A2ML1-TT dimer)
Map dataTEV cleaved A2ML1-TT dimer
Sample
  • Cell: A2ML1
    • Protein or peptide: Alpha-2-macroglobulin-like protein 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


peptidase inhibitor activity / regulation of endopeptidase activity / serine-type endopeptidase inhibitor activity / extracellular space / extracellular exosome
Similarity search - Function
Alpha-2-macroglobulin, TED domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor binding domain ...Alpha-2-macroglobulin, TED domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor binding domain / Macroglobulin domain MG4 / 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-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsNielsen NS / Zarantonello A / Andersen GR
Funding support Denmark, 1 items
OrganizationGrant numberCountry
LundbeckfondenR155-2015-2666 Denmark
CitationJournal: Nat Commun / Year: 2022
Title: Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.
Authors: Nadia Sukusu Nielsen / Alessandra Zarantonello / Seandean Lykke Harwood / Kathrine Tejlgård Jensen / Katarzyna Kjøge / Ida B Thøgersen / Leif Schauser / Jesper Lykkegaard Karlsen / ...Authors: Nadia Sukusu Nielsen / Alessandra Zarantonello / Seandean Lykke Harwood / Kathrine Tejlgård Jensen / Katarzyna Kjøge / Ida B Thøgersen / Leif Schauser / Jesper Lykkegaard Karlsen / Gregers R Andersen / Jan J Enghild /
Abstract: A2ML1 is a monomeric protease inhibitor belonging to the A2M superfamily of protease inhibitors and complement factors. Here, we investigate the protease-inhibitory mechanism of human A2ML1 and ...A2ML1 is a monomeric protease inhibitor belonging to the A2M superfamily of protease inhibitors and complement factors. Here, we investigate the protease-inhibitory mechanism of human A2ML1 and determine the structures of its native and protease-cleaved conformations. The functional inhibitory unit of A2ML1 is a monomer that depends on covalent binding of the protease (mediated by A2ML1's thioester) to achieve inhibition. In contrast to the A2M tetramer which traps proteases in two internal chambers formed by four subunits, in protease-cleaved monomeric A2ML1 disordered regions surround the trapped protease and may prevent substrate access. In native A2ML1, the bait region is threaded through a hydrophobic channel, suggesting that disruption of this arrangement by bait region cleavage triggers the extensive conformational changes that result in protease inhibition. Structural comparisons with complement C3/C4 suggest that the A2M superfamily of proteins share this mechanism for the triggering of conformational change occurring upon proteolytic activation.
History
DepositionNov 5, 2021-
Header (metadata) releaseApr 20, 2022-
Map releaseApr 20, 2022-
UpdateNov 2, 2022-
Current statusNov 2, 2022Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_13850.png

Downloads & links

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Map

FileDownload / File: emd_13850.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTEV cleaved A2ML1-TT dimer
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 512 pix.
= 331.264 Å		0.65 Å/pix.
x 512 pix.
= 331.264 Å		0.65 Å/pix.
x 512 pix.
= 331.264 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.647 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.035
Minimum - Maximum-0.12158364 - 0.24434075
Average (Standard dev.)-6.1909705e-05 (±0.005409431)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 331.264 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map B

Fileemd_13850_half_map_1.map
Annotationhalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_13850_half_map_2.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : A2ML1

EntireName: A2ML1
Components
  • Cell: A2ML1
    • Protein or peptide: Alpha-2-macroglobulin-like protein 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: A2ML1

SupramoleculeName: A2ML1 / type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: TEV cleaved and dimerized
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-2-macroglobulin-like protein 1

MacromoleculeName: Alpha-2-macroglobulin-like protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 159.339281 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ELPNYLVTLP ARLNFPSVQK VCLDLSPGYS DVKFTVTLET KDKTQKLLEY SGLKKRHLHC ISFLVPPPAG GTEEVATIRV SGVGNNISF EEKKKVLIQR QGNGTFVQTD KPLYTPGQQV YFRIVTMDSN FVPVNDKYSM VELQDPNSNR IAQWLEVVPE Q GIVDLSFQ ...String:
ELPNYLVTLP ARLNFPSVQK VCLDLSPGYS DVKFTVTLET KDKTQKLLEY SGLKKRHLHC ISFLVPPPAG GTEEVATIRV SGVGNNISF EEKKKVLIQR QGNGTFVQTD KPLYTPGQQV YFRIVTMDSN FVPVNDKYSM VELQDPNSNR IAQWLEVVPE Q GIVDLSFQ LAPEAMLGTY TVAVAEGKTF GTFSVEEYVL PKFKVEVVEP KELSTVQESF LVKICCRYTY GKPMLGAVQV SV CQKANTY WYREVEREQL PDKCRNLSGQ TDKTGCFSAP VDMATFDLIG YAYSHQINIV ATVVEEGTGV EANATQNIYI SPQ MGSMTF EDTSNFYHPN FPFSGKIRVR GHDDSFLKNH LVFLVIYGTN GTFNQTLVTD NNGLAPFTLE TSGWNGTDVS LEGK FQMED LVYNPEQVPR YYQNAYLHLR PFYSTTRSFL GIHRLNGPLK CGQPQEVLVD YYIDPADASP DQEISFSYYL IGKGS LVME GQKHLNSKKK GLKASFSLSL TFTSRLAPDP SLVIYAIFPS GGVVADKIQF SVEMCFDNQV SLGFSPSQQL PGAEVE LQL QAAPGSLCAL RAVDESVLLL RPDRELSNRS VYGMFPFWYG HYPYQVAEYD QCPVSGPWDF PQPLIDPMPQ GHSSQRS II WRPSFSEGTD LFSFFRDVGL KILSNAKIKK PVDCSHRSPE YSTAMGAGGG HPEAFESSTP LHQAEDSQVR QYFPETWL W DLFPIGNSGK EAVHVTVPDA ITEWKAMSFC TSQSRGFGLS PTVGLTAFKP FFVDLTLPYS VVRGESFRLT ATIFNYLKD CIRVQTDLAK SHEYQLESWA DSQTSSCLCA DDAKTHHWNI TAVKLGHINF TISTKILDSN EPCGGQKGFV PQKGRSDTLI KPVLVKPEG VLVEKTHSSL LCPKGKVASE SVSLELPVDI VPDSTKAYVT VLGDIMGTAL QNLDGLVQMP SGCGEQNMVL F APIIYVLQ YLEKAGLLTE EIRSRAVGFL EIGYQKELMY KHSNGSYSAF GERDGNGNTW LTAFVTKCFG QAQKFIFIDP KN IQDALKW MAGNQLPSGC YANVGNLLHT AMKGGVDDEV SLTAYVTAAL LEMGKDVDDP MVSQGLRCLK NSATSTTNLY TQA LLAYIF SLAGEMDIRN ILLKQLDQQA IISGESIYWS QKPTPSSNAS PWSEPAAVDV ELTAYALLAQ LTKPSLTQKE IAKA TSIVA WLAKQHNAYG GFSSTQDTVV ALQALAKYAT TAYMPSEEIN LVVKSTENFQ RTFNIQSVNR LVFQQDTLPN VPGMY TLEA SGQGCVYVQT VLRYNILPPT NMKTFSLSVE IGKARCEQPT SPRSLTLTIH TSYVGSRSSS NMAIVEVKML SGFSPM EGT NQLLLQQPLV KKVEFGTDTL NIYLDELIKN TQTYTFTISQ SVLVTNLKPA TIKVYDYYLP DEQATIQYSD PCE

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

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

BufferpH: 7.2
VitrificationCryogen name: PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.6 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 61.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 3.2.0)
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0) / Details: stochastic gradient descent
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2.0) / Number images used: 174680

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