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- EMDB-12943: (h-alpha2M)4 transient III state -

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Basic information

Entry
Database: EMDB / ID: EMD-12943
Title(h-alpha2M)4 transient III state
Map data(h-alpha2M)4 transient III state
Sample
  • Complex: Human alpha-2-macroglobulin transient III state
    • Protein or peptide: Alpha-2-macroglobulin
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 9.1 Å
AuthorsLuque D / Goulas T / Mata CP / Mendes SR / Gomis-Ruth FX / Caston JR
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
DepositionMay 14, 2021-
Header (metadata) releaseApr 13, 2022-
Map releaseApr 13, 2022-
UpdateMay 11, 2022-
Current statusMay 11, 2022Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_12943.png

Downloads & links

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Map

FileDownload / File: emd_12943.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation(h-alpha2M)4 transient III state
Voxel sizeX=Y=Z: 1.047 Å
Density
Contour LevelBy AUTHOR: 0.008
Minimum - Maximum-0.014037127 - 0.032060735
Average (Standard dev.)0.0002872933 (±0.0018007164)
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 transient III state

EntireName: Human alpha-2-macroglobulin transient III state
Components
  • Complex: Human alpha-2-macroglobulin transient III state
    • Protein or peptide: Alpha-2-macroglobulin

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Supramolecule #1: Human alpha-2-macroglobulin transient III state

SupramoleculeName: Human alpha-2-macroglobulin transient III state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
SequenceString: MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV SASLESVRG NRSLFTDLEA ENDVLHCVAF AVPKSSSNEE VMFLTVQVKG PTQEFKKRTT V MVKNEDSL VFVQTDKSIY KPGQTVKFRV VSMDENFHPL NELIPLVYIQ ...String:
MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV SASLESVRG NRSLFTDLEA ENDVLHCVAF AVPKSSSNEE VMFLTVQVKG PTQEFKKRTT V MVKNEDSL VFVQTDKSIY KPGQTVKFRV VSMDENFHPL NELIPLVYIQ DPKGNRIAQW QS FQLEGGL KQFSFPLSSE PFQGSYKVVV QKKSGGRTEH PFTVEEFVLP KFEVQVTVPK IIT ILEEEM NVSVCGLYTY GKPVPGHVTV SICRKYSDAS DCHGEDSQAF CEKFSGQLNS HGCF YQQVK TKVFQLKRKE YEMKLHTEAQ IQEEGTVVEL TGRQSSEITR TITKLSFVKV DSHFR QGIP FFGQVRLVDG KGVPIPNKVI FIRGNEANYY SNATTDEHGL VQFSINTTNV MGTSLT VRV NYKDRSPCYG YQWVSEEHEE AHHTAYLVFS PSKSFVHLEP MSHELPCGHT QTVQAHY IL NGGTLLGLKK LSFYYLIMAK GGIVRTGTHG LLVKQEDMKG HFSISIPVKS DIAPVARL L IYAVLPTGDV IGDSAKYDVE NCLANKVDLS FSPSQSLPAS HAHLRVTAAP QSVCALRAV DQSVLLMKPD AELSASSVYN LLPEKDLTGF PGPLNDQDNE DCINRHNVYI NGITYTPVSS TNEKDMYSF LEDMGLKAFT NSKIRKPKMC PQLQQYEMHG PEGLRVGFYE SDVMGRGHAR L VHVEEPHT ETVRKYFPET WIWDLVVVNS AGVAEVGVTV PDTITEWKAG AFCLSEDAGL GI SSTASLR AFQPFFVELT MPYSVIRGEA FTLKATVLNY LPKCIRVSVQ LEASPAFLAV PVE KEQAPH CICANGRQTV SWAVTPKSLG NVNFTVSAEA LESQELCGTE VPSVPEHGRK DTVI KPLLV EPEGLEKETT FNSLLCPSGG EVSEELSLKL PPNVVEESAR ASVSVLGDIL GSAMQ NTQN LLQMPYGCGE QNMVLFAPNI YVLDYLNETQ QLTPEIKSKA IGYLNTGYQR QLNYKH YDG SYSTFGERYG RNQGNTWLTA FVLKTFAQAR AYIFIDEAHI TQALIWLSQR QKDNGCF RS SGSLLNNAIK GGVEDEVTLS AYITIALLEI PLTVTHPVVR NALFCLESAW KTAQEGDH G SHVYTKALLA YAFALAGNQD KRKEVLKSLN EEAVKKDNSV HWERPQKPKA PVGHFYEPQ APSAEVEMTS YVLLAYLTAQ PAPTSEDLTS ATNIVKWITK QQNAQGGFSS TQDTVVALHA LSKYGAATF TRTGKAAQVT IQSSGTFSSK FQVDNNNRLL LQQVSLPELP GEYSMKVTGE G CVYLQTSL KYNILPEKEE FPFALGVQTL PQTCDEPKAH TSFQISLSVS YTGSRSASNM AI VDVKMVS GFIPLKPTVK MLERSNHVSR TEVSSNHVLI YLDKVSNQTL SLFFTVLQDV PVR DLKPAI VKVYDYYETD EFAIAEYNAP CSKDLGNA

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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
VitrificationCryogen name: ETHANE / Instrument: LEICA EM CPC

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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: 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
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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1625000
CTF correctionSoftware - Name: CTFFIND (ver. 4.1)
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.1)
Final 3D classificationSoftware - Name: RELION (ver. 2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.1)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 9.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.1) / Number images used: 23998

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER

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