- PDB-8d8o: Cryo-EM structure of substrate unbound PAPP-A -
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Basic information
Entry
Database: PDB / ID: 8d8o
Title
Cryo-EM structure of substrate unbound PAPP-A
Components
Pappalysin-1
Keywords
HYDROLASE / Metalloprotease / Metal-binding
Function / homology
Function and homology information
pappalysin-1 / response to follicle-stimulating hormone / protein metabolic process / response to dexamethasone / female pregnancy / protein catabolic process / metalloendopeptidase activity / metallopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cell surface receptor signaling pathway ...pappalysin-1 / response to follicle-stimulating hormone / protein metabolic process / response to dexamethasone / female pregnancy / protein catabolic process / metalloendopeptidase activity / metallopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cell surface receptor signaling pathway / proteolysis / extracellular space / zinc ion binding / extracellular region Similarity search - Function
Journal: Nat Commun / Year: 2022 Title: Structure of the PAPP-A complex reveals mechanism of substrate recognition. Authors: Russell A Judge / Janani Sridar / Kathryn Tunyasuvunakool / Rinku Jain / John C K Wang / Christna Ouch / Jun Xu / Amirhossein Mafi / Aaron H Nile / Clint Remarcik / Corey L Smith / Crystal ...Authors: Russell A Judge / Janani Sridar / Kathryn Tunyasuvunakool / Rinku Jain / John C K Wang / Christna Ouch / Jun Xu / Amirhossein Mafi / Aaron H Nile / Clint Remarcik / Corey L Smith / Crystal Ghosh / Chen Xu / Vincent Stoll / John Jumper / Amoolya H Singh / Dan Eaton / Qi Hao / Abstract: Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are ...Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are metalloproteases that mediate IGF bioavailability through cleavage of IGF binding proteins (IGFBPs). Here, we present single-particle cryo-EM structures of the catalytically inactive mutant PAPP-A (E483A) in complex with a peptide from its substrate IGFBP5 (PAPP-A) and also in its substrate-free form, by leveraging the power of AlphaFold to generate a high quality predicted model as a starting template. We show that PAPP-A is a flexible trans-dimer that binds IGFBP5 via a 25-amino acid anchor peptide which extends into the metalloprotease active site. This unique IGFBP5 anchor peptide that mediates the specific PAPP-A-IGFBP5 interaction is not found in other PAPP-A substrates. Additionally, we illustrate the critical role of the PAPP-A central domain as it mediates both IGFBP5 recognition and trans-dimerization. We further demonstrate that PAPP-A trans-dimer formation and distal inter-domain interactions are both required for efficient proteolysis of IGFBP4, but dispensable for IGFBP5 cleavage. Together the structural and biochemical studies reveal the mechanism of PAPP-A substrate binding and selectivity.
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