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TitleCryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 3033, Year 2022
Publish dateMay 31, 2022
AuthorsNadia 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 /
PubMed AbstractA2ML1 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.
External linksNat Commun / PubMed:35641520 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.88 - 4.4 Å
Structure data

13847

7q5z

EMDB-13847, PDB-7q5z:
Cryo-EM structure of native human A2ML1
Method: EM (single particle) / Resolution: 3.25 Å

13848

7q60

EMDB-13848, PDB-7q60:
Structure of TEV cleaved A2ML1 (A2ML1-TE)
Method: EM (single particle) / Resolution: 3.13 Å

13849

7q61

EMDB-13849, PDB-7q61:
Structure of TEV conjugated A2ML1 (A2ML1-TC)
Method: EM (single particle) / Resolution: 2.88 Å

13850

7q62

EMDB-13850, PDB-7q62:
Structure of TEV cleaved A2ML1 dimer (A2ML1-TT dimer)
Method: EM (single particle) / Resolution: 3.18 Å

PDB-7q1y:
X-ray structure of human A2ML1
Method: X-RAY DIFFRACTION / Resolution: 4.4 Å

Chemicals

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

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / protease inhibitor / thioester protein / A2M family / protease / inhibitor / thioester

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