7UFG
Cryo-EM structure of PAPP-A in complex with IGFBP5
Summary for 7UFG
| Entry DOI | 10.2210/pdb7ufg/pdb |
| EMDB information | 26475 |
| Descriptor | Pappalysin-1, Insulin-like growth factor-binding protein 5, ZINC ION (3 entities in total) |
| Functional Keywords | metalloprotease, metal-binding, hydrolase, hydrolase-hormone complex, hydrolase/hormone |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 414566.78 |
| Authors | Judge, R.A.,Jain, R.,Hao, Q.,Ouch, C.,Sridar, J.,Smith, C.L.,Wang, J.C.K.,Eaton, D. (deposition date: 2022-03-22, release date: 2022-09-28, Last modification date: 2024-10-23) |
| Primary citation | Judge, R.A.,Sridar, J.,Tunyasunvunakool, K.,Jain, R.,Wang, J.C.K.,Ouch, C.,Xu, J.,Mafi, A.,Nile, A.H.,Remarcik, C.,Smith, C.L.,Ghosh, C.,Xu, C.,Stoll, V.,Jumper, J.,Singh, A.H.,Eaton, D.,Hao, Q. Structure of the PAPP-ABP5 complex reveals mechanism of substrate recognition Nat Commun, 13:5500-, 2022 Cited by PubMed 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 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. PubMed: 36127359DOI: 10.1038/s41467-022-33175-2 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.28 Å) |
Structure validation
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