+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-13848 | |||||||||
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Title | Structure of TEV cleaved A2ML1 (A2ML1-TE) | |||||||||
Map data | full map TEV cleaved empty A2ML1 | |||||||||
Sample |
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Keywords | protease inhibitor / thioester / IMMUNE SYSTEM | |||||||||
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 | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.13 Å | |||||||||
Authors | Nielsen NS / Zarantonello A | |||||||||
Funding support | Denmark, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_13848.map.gz | 52 MB | EMDB map data format | |
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Header (meta data) | emd-13848-v30.xml emd-13848.xml | 11.2 KB 11.2 KB | Display Display | EMDB header |
Images | emd_13848.png | 75 KB | ||
Filedesc metadata | emd-13848.cif.gz | 5.9 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-13848 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13848 | HTTPS FTP |
-Validation report
Summary document | emd_13848_validation.pdf.gz | 470.7 KB | Display | EMDB validaton report |
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Full document | emd_13848_full_validation.pdf.gz | 470.3 KB | Display | |
Data in XML | emd_13848_validation.xml.gz | 6.5 KB | Display | |
Data in CIF | emd_13848_validation.cif.gz | 7.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13848 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13848 | HTTPS FTP |
-Related structure data
Related structure data | 7q60MC 7q1yC 7q5zC 7q61C 7q62C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_13848.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | full map TEV cleaved empty A2ML1 | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.10421 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
-Entire : A2ML1
Entire | Name: A2ML1 |
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Components |
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-Supramolecule #1: A2ML1
Supramolecule | Name: A2ML1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Alpha-2-macroglobulin-like protein 1
Macromolecule | Name: Alpha-2-macroglobulin-like protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 159.339281 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 UniProtKB: Alpha-2-macroglobulin-like protein 1 |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.2 |
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Vitrification | Cryogen name: PROPANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 61.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.6 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2.0) / Number images used: 291904 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0) / Details: stochastic gradient descen |
Final angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0) |