Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2
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 i...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-12-01
|
| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-022-00502-2 |
| _version_ | 1797977580086755328 |
|---|---|
| author | Qihang 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 |
| author_facet | Qihang 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 |
| author_sort | Qihang Zhong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T05:09:14Z |
| format | Article |
| id | doaj.art-01d7f2bbc9d44d8eb812bcc73a7aae5f |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-04-11T05:09:14Z |
| publishDate | 2022-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-01d7f2bbc9d44d8eb812bcc73a7aae5f2022-12-25T12:05:07ZengNature Publishing GroupCell Discovery2056-59682022-12-018111710.1038/s41421-022-00502-2Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2Qihang Zhong0Honglei Chu1Guopeng Wang2Cheng Zhang3Rong Li4Fusheng Guo5Xinlu Meng6Xiaoguang Lei7Youli Zhou8Ruobing Ren9Lin Tao10Ningning Li11Ning Gao12Yuan Wei13Jie Qiao14Jing Hang15Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third HospitalCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third HospitalState Key Laboratory of Membrane Biology, School of Life Sciences, Peking UniversityDepartment of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & InstituteCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third HospitalBeijing National Laboratory for Molecular Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking UniversityCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third HospitalBeijing National Laboratory for Molecular Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking UniversitySchool of Life and Health Sciences, The Chinese University of Hong KongSchool of Life and Health Sciences, The Chinese University of Hong KongDepartment of Orthopedics, First Hospital of China Medical UniversityState Key Laboratory of Membrane Biology, School of Life Sciences, Peking UniversityState Key Laboratory of Membrane Biology, School of Life Sciences, Peking UniversityCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third HospitalCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third HospitalCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third HospitalAbstract 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.https://doi.org/10.1038/s41421-022-00502-2 |
| spellingShingle | Qihang 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 Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2 Cell Discovery |
| title | Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2 |
| title_full | Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2 |
| title_fullStr | Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2 |
| title_full_unstemmed | Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2 |
| title_short | Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2 |
| title_sort | structural insights into the covalent regulation of papp a activity by prombp and stc2 |
| url | https://doi.org/10.1038/s41421-022-00502-2 |
| work_keys_str_mv | AT qihangzhong structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT hongleichu structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT guopengwang structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT chengzhang structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT rongli structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT fushengguo structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT xinlumeng structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT xiaoguanglei structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT youlizhou structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT ruobingren structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT lintao structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT ningningli structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT ninggao structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT yuanwei structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT jieqiao structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 AT jinghang structuralinsightsintothecovalentregulationofpappaactivitybyprombpandstc2 |