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TitleStructure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 6084, Year 2022
Publish dateOct 18, 2022
AuthorsSara Dam Kobberø / Michael Gajhede / Osman Asghar Mirza / Søren Kløverpris / Troels Rønn Kjær / Jakob Hauge Mikkelsen / Thomas Boesen / Claus Oxvig /
PubMed AbstractThe metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single- ...The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single-particle cryo-electron microscopy (cryo-EM), we here report the structure of PAPP-A in complex with its endogenous inhibitor, stanniocalcin-2 (STC2), neither of which have been reported before. The highest resolution (3.1 Å) was obtained for the STC2 subunit and the N-terminal approximately 1000 residues of the PAPP-A subunit. The 500 kDa 2:2 PAPP-A·STC2 complex is a flexible multidomain ensemble with numerous interdomain contacts. In particular, a specific disulfide bond between the subunits of STC2 and PAPP-A prevents dissociation, and interactions between STC2 and a module located in the very C-terminal end of the PAPP-A subunit prevent binding of its main substrate, IGFBP-4. While devoid of activity towards IGFBP-4, the active site cleft of the catalytic domain is accessible in the inhibited PAPP-A·STC2 complex, as shown by its ability to hydrolyze a synthetic peptide derived from IGFBP-4. Relevant to multiple human pathologies, this unusual mechanism of proteolytic inhibition may support the development of specific pharmaceutical agents, by which IGF signaling can be indirectly modulated.
External linksNat Commun / PubMed:36257932 / PubMed Central
MethodsEM (single particle)
Resolution3.06 - 5.02 Å
Structure data

EMDB-15217: PAPP-A dimer in complex with a dimer of the inhibitor STC2
Method: EM (single particle) / Resolution: 4.05 Å

EMDB-15219: PAPP-A dimer in complex with endogenous STC2 inhibitor.
Method: EM (single particle) / Resolution: 5.02 Å

15220

8a7d

EMDB-15220, PDB-8a7d:
Partial dimer complex of PAPP-A and its inhibitor STC2
Method: EM (single particle) / Resolution: 3.06 Å

15221

8a7e

EMDB-15221, PDB-8a7e:
PAPP-A dimer in complex with its inhibitor STC2
Method: EM (single particle) / Resolution: 5.02 Å

Chemicals

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

ChemComp-ZN:
Unknown entry

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsHYDROLASE / Metzincin metalloprotease Inhibitor complex

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