7Y5Q
Structure of 1:1 PAPP-A.STC2 complex(half map)
Summary for 7Y5Q
| Entry DOI | 10.2210/pdb7y5q/pdb |
| EMDB information | 33622 |
| Descriptor | Maltose/maltodextrin-binding periplasmic protein,Pappalysin-1, Stanniocalcin-2, ZINC ION (3 entities in total) |
| Functional Keywords | hydrolase, metal binding protein |
| Biological source | Escherichia coli K-12 More |
| Total number of polymer chains | 3 |
| Total formula weight | 466160.79 |
| Authors | Zhong, Q.H.,Chu, H.L.,Wang, G.P.,Zhang, C.,Wei, Y.,Qiao, J.,Hang, J. (deposition date: 2022-06-17, release date: 2023-01-11, Last modification date: 2024-11-06) |
| Primary citation | Zhong, Q.,Chu, H.,Wang, G.,Zhang, C.,Li, R.,Guo, F.,Meng, X.,Lei, X.,Zhou, Y.,Ren, R.,Tao, L.,Li, N.,Gao, N.,Wei, Y.,Qiao, J.,Hang, J. Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2. Cell Discov, 8:137-137, 2022 Cited by PubMed Abstract: Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2). However, the structural basis of PAPP-A proteolysis and the mechanistic differences between these two modulators are poorly understood. Here we present two cryo-EM structures of endogenous purified PAPP-A in complex with either proMBP or STC2. Both modulators form 2:2 heterotetramer with PAPP-A and establish extensive interactions with multiple domains of PAPP-A that are distal to the catalytic cleft. This exosite-binding property results in a steric hindrance to prevent the binding and cleavage of IGFBPs, while the IGFBP linker region-derived peptides harboring the cleavage sites are no longer sensitive to the modulator treatment. Functional investigation into proMBP-mediated PAPP-A regulation in selective intrauterine growth restriction (sIUGR) pregnancy elucidates that PAPP-A and proMBP collaboratively regulate extravillous trophoblast invasion and the consequent fetal growth. Collectively, our work reveals a novel covalent exosite-competitive inhibition mechanism of PAPP-A and its regulatory effect on placental function. PubMed: 36550107DOI: 10.1038/s41421-022-00502-2 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.8 Å) |
Structure validation
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