ArticleThe Biochemical journal2002
Substrate specificity of the metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) assessed by mutagenesis and analysis of synthetic peptides: substrate residues distant from the scissile bond are critical for proteolysis.
Article in The Biochemical journal, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 84 citations in OpenAlex.
- Prognostic Values of Pregnancy-Associated Plasma Protein-A and IGF-Binding Protein-4 Fragments in Patients with Acute Myocardial Infarction.Journal of clinical medicine · 2026Article
- Left Ventricular and Right Ventricular Hypertrophy Modelling to Study PAPP-A-Mediated IGFBP-4 Cleavage-a Mechanism That Regulates IGF Bioavailability in Adult Rats.International journal of molecular sciences · 2026Article
- Zinc Metalloprotease SlMEP1: An Essential Factor Required for Fungal Virulence inJournal of fungi (Basel, Switzerland) · 2025Article
- Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition.Communications chemistry · 2023Article
- Article
- PAPP-A-Specific IGFBP-4 Proteolysis in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.International journal of molecular sciences · 2023Article
- Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2.Cell discovery · 2022Article
- Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism.Nature communications · 2022Article
- Structure of the PAPP-ANature communications · 2022Article
- Leptolysin, aFrontiers in cellular and infection microbiology · 2022Article
- Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis?Frontiers in endocrinology · 2022Review
- Genome-Wide Identification of M35 Family Metalloproteases inInternational journal of molecular sciences · 2020Article
- Article
- Recombinant PAPP-A resistant insulin-like growth factor binding protein 4 (dBP4) inhibits angiogenesis and metastasis in a murine model of breast cancer.BMC cancer · 2018Article
- Prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in ST-segment elevation myocardial infarction.Cardiovascular diabetology · 2018Observational
- Differential Functions of Two Metalloproteases,Frontiers in microbiology · 2018Article
- Insulin- like Growth Factor-Binding Protein Action in Bone Tissue: A Key Role for Pregnancy- Associated Plasma Protein-A.Frontiers in endocrinology · 2018Review
- Pregnancy-associated plasma protein-A is a stronger predictor for adverse cardiovascular outcomes after acute coronary syndrome in type-2 diabetes mellitus.Cardiovascular diabetology · 2017Article
- The role of PAPP-A in the IGF system: location, location, location.Journal of cell communication and signaling · 2015Article
- Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis.The Journal of biological chemistry · 2015Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Human pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor (IGF) binding protein-4 (IGFBP-4), causing a dramatic reduction in its affinity for IGF-I and -II. Through this mechanism, PAPP-A is a regulator of IGF bioactivity in several systems, including the human ovary and the cardiovascular system. PAPP-A belongs to the metzincin superfamily of zinc metalloproteinases, and is the founding member of a fifth metzincin family, the pappalysins. Herein, we first determined that PAPP-A cleaves IGFBP-4 at a single site (Met-135/Lys-136), and we analysed the influence of ionic strength, pH and zinc ion concentration on the cleavage reaction. Secondly, we sought to delineate the role of substrate residues in PAPP-A-mediated cleavage by the construction and analysis of 30 IGFBP-4 mutants in which various residues were replaced by alanine, by the analysis of eight mutants of IGFBP-5 (found recently to be a second PAPP-A substrate), and by cleavage analysis of synthetic peptides derived from IGFBP-4. Our data reveal a complex mode of substrate recognition and/or binding, pointing at important roles for several basic residues located up to 16 residues N-terminal to the scissile bond. An unexpected parallel can be drawn with an intracellular enzyme, the mitochondrial processing peptidase, that may help us to understand properties of the pappalysins. Further, proteinase-resistant variants of IGFBP-4 and -5, presented here, will be useful tools for the study of proteolysis in cell-based systems, and our finding that a synthetic peptide can be cleaved by PAPP-A provides the basis for development of quantitative assays for the investigation of PAPP-A enzyme kinetics.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.