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| Title | Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α-macroglobulin. |
|---|---|
| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 119, Issue 19, Page e2200102119, Year 2022 |
| Publish date | May 10, 2022 |
 Authors | Daniel Luque / Theodoros Goulas / Carlos P Mata / Soraia R Mendes / F Xavier Gomis-Rüth / José R Castón /    |
| PubMed 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. |
 External links | Proc Natl Acad Sci U S A / PubMed:35500114 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.6 - 12.0 Å |
| Structure data | EMDB-12747, PDB-7o7l: EMDB-12748, PDB-7o7m: EMDB-12750, PDB-7o7n: EMDB-12751, PDB-7o7o: EMDB-12752, PDB-7o7p: EMDB-12753, PDB-7o7q: EMDB-12754, PDB-7o7r: EMDB-12755, PDB-7o7s:  EMDB-12941: (h-alpha2M)4 transient I state  EMDB-12942: (h-alpha2M)4 transient II state  EMDB-12943: (h-alpha2M)4 transient III state  EMDB-12944: (h-alpha2M)4 transient IV state |
| Chemicals |  ChemComp-NAG: |
| Source |
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 Keywords |  PROTEIN BINDING / alpha2-macroglobulin / proteinase / serum proteostasis / hydrolase inhibitor |
