Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism

Sara Dam Kobberø, Michael Gajhede, Osman Asghar Mirza, Søren Kløverpris, Troels Rønn Kjær, Jakob Hauge Mikkelsen, Thomas Boesen and Claus Oxvig ()
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Sara Dam Kobberø: Aarhus University
Michael Gajhede: University of Copenhagen
Osman Asghar Mirza: University of Copenhagen
Søren Kløverpris: Aarhus University
Troels Rønn Kjær: Aarhus University
Jakob Hauge Mikkelsen: Aarhus University
Thomas Boesen: Aarhus University
Claus Oxvig: Aarhus University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33698-8

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