Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2

Cell Discovery

Article

Fusheng Guo¹  Xiaoguang Lei²  Xinlu Meng³  Rong Li⁴  Honglei Chu⁴  Jing Hang⁴  Qihang Zhong⁴  Yuan Wei⁴  Jie Qiao⁵  Cheng Zhang⁶  Lin Tao⁷  Youli Zhou⁸  Ruobing Ren⁹  Ningning Li^1,10  Guopeng Wang^1,10  Ning Gao^1,11 

[1] Beijing 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 University, Beijing, China;Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China;Beijing 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 University, Beijing, China;Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China;Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China;Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China;Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China;Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China;Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China;National Clinical Research Center for Obstetrics and Gynecology, Beijing, China;Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China;Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China;Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China;National Clinical Research Center for Obstetrics and Gynecology, Beijing, China;Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China;Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China;Department of Orthopedics, First Hospital of China Medical University, Shenyang, Liaoning, China;School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, China;School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, China;Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China;State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China;State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China;Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China;

DOI  :  10.1038/s41421-022-00502-2

 received in 2022-10-23, accepted in 2022-11-25,  发布年份 2022

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2022

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