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Structure paper

TitleThree cryo-EM structures of complement C3d-bound alpha M beta 2 reveal an unexpected layer of dynamics for alpha I-containing integrin receptors.
Journal, issue, pagesSci Adv, Vol. 12, Page eaea7241-eaea7241, Year 2026
Publish dateAug 29, 2024 (structure data deposition date)
AuthorsJosefine Lorentzen / Marlene Uglebjerg Fruergaard / Szilvia Lukácsi / Martin Høgholm Jørgensen / Timo Lambertus Gerardus van Veghel / Rasmus Kjeldsen Jensen / Krzysztof Jakub Pietrzak-Lichwa / Zsuzsa Bajtay / Václav Hořejší / Rasmus Kock Flygaard / Daan Vorselen / Simon Arnold Mortensen / Gregers Rom Andersen /
PubMed AbstractIntegrins are heterodimeric membrane proteins acting as mechanosensing receptors. Nine human α-subunits contain a ligand binding αI domain, but how ligands activate αI integrins are not understood. ...Integrins are heterodimeric membrane proteins acting as mechanosensing receptors. Nine human α-subunits contain a ligand binding αI domain, but how ligands activate αI integrins are not understood. We present cryo-EM structures of the αI integrin αβ in complex with the C3d ligand. The ligand-bound αI domain appears to have two major opposite orientations relative to the β subunit. Ligand binding induces an ordered conformation of the α internal ligand region that is tightly packed between the α β-propeller and the β βI-domain. Recognition of the internal ligand induces an open βI conformation practically identical to that of ligand-bound αI-less integrins confirming that ligand binding and signaling are coupled by a universal mechanism across all integrins. Integration of our findings with prior data allows us to propose a model for C3dg/iC3b-bound αβ in the phagocytotic cup and outline mechanistic models for external ligand-induced activation of αβ.
External linksSci Adv / PubMed:42102216 / PubMed Central
MethodsX-ray diffraction / EM (single particle)
Resolution2.17 - 3.94 Å
Structure data

PDB-9gmu:
Structure ofhuman aM ligand binding domain in complex with the aCR3 nanobody
Method: X-RAY DIFFRACTION / Resolution: 3.8 Å

PDB-9hll:
murine aM I-domain in complex with nanobody aCR3
Method: X-RAY DIFFRACTION / Resolution: 2.17 Å

PDB-9rm9:
Cryo-EM structure of alphaM/beta2 headpiece complex without alphaM I-domain - the consensus map from alphaM/beta2:C3d-anti-CR3-Nb headpiece complex
Method: ELECTRON MICROSCOPY / Resolution: 2.6 Å

PDB-9rma:
Cryo-EM structure of alphaM I-domain:C3d-anti-CR3-Nb complex focused refinement from the alphaM/beta2:C3d-anti-CR3-Nb headpiece complex
Method: ELECTRON MICROSCOPY / Resolution: 3.94 Å

PDB-9t3y:
Cryo-EM structure of alphaM/beta2:C3d-anti-CR3-Nb headpiece complex (HPO2 3D class reconstruction)
Method: ELECTRON MICROSCOPY / Resolution: 3.44 Å

PDB-9t5v:
Cryo-EM structure of alphaM/beta2:C3d-anti-CR3-Nb headpiece complex (HPO1 3D class reconstruction)
Method: ELECTRON MICROSCOPY / Resolution: 3.06 Å

PDB-9t5w:
Cryo-EM structure of mutant R61H alphaM/beta2 headpiece complex
Method: ELECTRON MICROSCOPY / Resolution: 2.74 Å

PDB-9t5z:
Cryo-EM structure of alphaM/beta2:MEM148-Fab headpiece complex (without alphaM I-domain)
Method: ELECTRON MICROSCOPY / Resolution: 3.1 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-SO4:
SULFATE ION

ChemComp-HOH:
WATER

ChemComp-CA:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MN:
Unknown entry

Source
  • homo sapiens (human)
  • lama glama (llama)
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / integrin receptor / ligand binding domain / antibody / VHH / complement / phagocytosis / integrin / opsonisation

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