ArticleNature communications2022
Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Unravelling the Impact of Diabetes on Insulin-like Growth Factor (IGF) Axis Signalling in Mesenchymal Stem Cells Isolated from the Bone of Knee Joints.Bioengineering (Basel, Switzerland) · 2026Article
- Size in small-for-gestational-age neonates correlates with insulin-like growth factor-binding protein proteolysis and insulin-like growth factor-I bioavailability.Journal of the Endocrine Society · 2026Article
- High Expression of PAPP-A Predicts Poor Outcomes in Oestrogen Receptor-Positive Breast Cancer Patients.Cancer medicine · 2026Article
- Regulation and function of insulin and insulin-like growth factor receptor signalling.Nature reviews. Molecular cell biology · 2025Review
- Biochemical and structural characterization of the human gut microbiome metallopeptidase IgAse provides insight into its unique specificity for the Fab' region of IgA1 and IgA2.PLoS pathogens · 2025Article
- The IGF System and Aging.Endocrine reviews · 2025Review
- The Proteinase PAPP-A has Deep Evolutionary Roots Outside of the IGF System.Genome biology and evolution · 2025Article
- Dissecting Cytophagalysin: Structural and Biochemical Studies of a Bacterial Pappalysin-Family Metallopeptidase.Biomolecules · 2024Article
- Article
- The pro-atherogenic enzyme PAPP-A is active in eluates from human carotid and femoral atherosclerotic plaques.Atherosclerosis plus · 2024Article
- The metalloproteinase PAPP-A is required for IGF-dependent chondrocyte differentiation and organization.Scientific reports · 2024Article
- Stanniocalcin Protein Expression in Female Reproductive Organs: Literature Review and Public Cancer Database Analysis.Endocrinology · 2024Review
- Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches.International journal of molecular sciences · 2024Review
- Implication of Pappalysins and Stanniocalcins in the Bioavailability of IGF-I in Children With Type 1 Diabetes Mellitus.Journal of the Endocrine Society · 2024Article
- Review
- The role of pregnancy associated plasma protein-A in triple negative breast cancer: a promising target for achieving clinical benefits.Journal of biomedical science · 2024Review
- Pregnancy associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) but not PAPP-A are associated with circulating total IGF-1 in a human adult population.Scientific reports · 2024Article
- AlphaFold2 enables accurate deorphanization of ligands to single-pass receptors.bioRxiv : the preprint server for biology · 2023Article
- Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition.Communications chemistry · 2023Article
- Stanniocalcin-2 inhibits skeletal muscle growth and is upregulated in functional overload-induced hypertrophy.Physiological reports · 2023Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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