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Publication Abstract from PubMed

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(BP5)) 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.

Structure of the PAPP-A(BP5) complex reveals mechanism of substrate recognition.,Judge RA, Sridar J, Tunyasuvunakool K, Jain R, Wang JCK, Ouch C, Xu J, Mafi A, Nile AH, Remarcik C, Smith CL, Ghosh C, Xu C, Stoll V, Jumper J, Singh AH, Eaton D, Hao Q Nat Commun. 2022 Sep 20;13(1):5500. doi: 10.1038/s41467-022-33175-2. PMID:36127359^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.