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Structure paper

TitleCryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α-macroglobulin.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 119, Issue 19, Page e2200102119, Year 2022
Publish dateMay 10, 2022
AuthorsDaniel Luque / Theodoros Goulas / Carlos P Mata / Soraia R Mendes / F Xavier Gomis-Rüth / José R Castón /
PubMed AbstractHuman 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 linksProc Natl Acad Sci U S A / PubMed:35500114 / PubMed Central
MethodsEM (single particle)
Resolution3.6 - 12.0 Å
Structure data

EMDB-12747, PDB-7o7l:
(h-alpha2M)4 native I
Method: EM (single particle) / Resolution: 4.5 Å

EMDB-12748, PDB-7o7m:
(h-alpha2M)4 native II
Method: EM (single particle) / Resolution: 6.6 Å

EMDB-12750, PDB-7o7n:
(h-alpha2M)4 semiactivated I state
Method: EM (single particle) / Resolution: 7.3 Å

EMDB-12751, PDB-7o7o:
(h-alpha2M)4 semiactivated II state
Method: EM (single particle) / Resolution: 4.8 Å

EMDB-12752, PDB-7o7p:
(h-alpha2M)4 activated state
Method: EM (single particle) / Resolution: 4.6 Å

EMDB-12753, PDB-7o7q:
(h-alpha2M)4 trypsin-activated state
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-12754, PDB-7o7r:
(h-alpha2M)4 plasmin-activated I state
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-12755, PDB-7o7s:
(h-alpha2M)4 plasmin-activated II state
Method: EM (single particle) / Resolution: 4.3 Å

EMDB-12941: (h-alpha2M)4 transient I state
Method: EM (single particle) / Resolution: 5.2 Å

EMDB-12942: (h-alpha2M)4 transient II state
Method: EM (single particle) / Resolution: 12.0 Å

EMDB-12943: (h-alpha2M)4 transient III state
Method: EM (single particle) / Resolution: 9.1 Å

EMDB-12944: (h-alpha2M)4 transient IV state
Method: EM (single particle) / Resolution: 9.3 Å

Chemicals

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

Source
  • homo sapiens (human)
  • Human (human)
KeywordsPROTEIN BINDING / alpha2-macroglobulin / proteinase / serum proteostasis / hydrolase inhibitor

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