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Structure paper

TitleStructural insights into the covalent regulation of PAPP-A activity by proMBP and STC2.
Journal, issue, pagesCell Discov, Vol. 8, Issue 1, Page 137, Year 2022
Publish dateDec 22, 2022
AuthorsQihang Zhong / Honglei Chu / Guopeng Wang / Cheng Zhang / Rong Li / Fusheng Guo / Xinlu Meng / Xiaoguang Lei / Youli Zhou / Ruobing Ren / Lin Tao / Ningning Li / Ning Gao / Yuan Wei / Jie Qiao / Jing Hang /
PubMed AbstractOriginally 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 ...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.
External linksCell Discov / PubMed:36550107 / PubMed Central
MethodsEM (single particle)
Resolution3.45 - 4.16 Å
Structure data

33621

7y5n

EMDB-33621, PDB-7y5n:
Structure of 1:1 PAPP-A.ProMBP complex(half map)
Method: EM (single particle) / Resolution: 3.45 Å

33622

7y5q

EMDB-33622, PDB-7y5q:
Structure of 1:1 PAPP-A.STC2 complex(half map)
Method: EM (single particle) / Resolution: 3.8 Å

34738

8hgg

EMDB-34738: Structure of 2:2 PAPP-A.ProMBP comple
PDB-8hgg: Structure of 2:2 PAPP-A.ProMBP complex
Method: EM (single particle) / Resolution: 3.64 Å

34739

8hgh

EMDB-34739, PDB-8hgh:
Structure of 2:2 PAPP-A.STC2 complex
Method: EM (single particle) / Resolution: 4.16 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ZN:
Unknown entry

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
  • escherichia coli k-12 (bacteria)
KeywordsMETAL BINDING PROTEIN/HYDROLASE / Hydrolase / METAL BINDING PROTEIN-HYDROLASE complex / METAL BINDING PROTEIN / Complex

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