Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 26; pp. 1 - 10
• Main Authors: Hart, Kaitlin N., Stocker, William A., Nagykery, Nicholas G., Walton, Kelly L., Harrison, Craig A., Donahoe, Patricia K., Pépin, David, Thompson, Thomas B.
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 29.06.2021
• Subjects: Activin; Antagonists; Antibodies; Binding; Biological Sciences; Crystal structure; Fetuses; Folliculogenesis; Growth factors; Immunotherapy; Ligands; Muellerian duct; Receptors; Sex differentiation; Toxins; Transforming growth factor-b
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2104809118

Anti-Müllerian hormone (AMH), or Müllerian-inhibiting substance, is a protein hormone that promotes Müllerian duct regression during male fetal sexual differentiation and regulation of folliculogenesis in women. AMH is a member of the transforming growth factor beta (TGF-β) family, which has evolved to signal through its own dedicated type II receptor, AMH receptor type II (AMHR2). Structures of other TGF-β family members have revealed how ligands infer specificity for their cognate receptors; however, it is unknown how AMH binds AMHR2 at the molecular level. Therefore, in this study, we solved the X-ray crystal structure of AMH bound to the extracellular domain of AMHR2 to a resolution of 2.6Å. The structure reveals that while AMH binds AMHR2 in a similar location to Activin and BMP ligand binding to their type II receptors, differences in both AMH and AMHR2 account for a highly specific interaction. Furthermore, using an AMH responsive cell-based luciferase assay, we show that a conformation in finger 1 of AMHR2 and a salt bridge formed by K534 on AMH and D81/E84 of AMHR2 are key to the AMH/AMHR2 interaction. Overall, our study highlights howAMH engages AMHR2 using a modified paradigm of receptor binding facilitated by modifications to the three-finger toxin fold of AMHR2. Furthermore, understanding these elements contributing to the specificity of binding will help in the design of agonists or antagonists or the selection of antibody therapies.