EMD-33621

Single-particle
3.45 Å
EMD-33621 Deposition: 17/06/2022
Map released: 11/01/2023
Last modified: 23/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-33621

Structure of 1:1 PAPP-A.ProMBP complex(half map)

EMD-33621

Single-particle
3.45 Å
EMD-33621 Deposition: 17/06/2022
Map released: 11/01/2023
Last modified: 23/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Structure of 1:1 PAPP-A/ProMBP complex(half map)
Fitted models: 7y5n (Avg. Q-score: 0.476)

Deposition Authors: Zhong QH, Chu HL, Wang GP, Zhang C, Wei Y, Qiao J , Hang J
Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2.
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
(2022) Cell Discov , 8 , 137 - 137
PUBMED: 36550107
DOI: doi:10.1038/s41421-022-00502-2
ISSN: 2056-5968
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.