Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family
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...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 26; pp. 1 - 10 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Washington
National Academy of Sciences
29.06.2021
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: K.N.H., W.A.S., N.G.N., K.L.W., C.A.H., P.K.D., D.P., and T.B.T. designed research; K.N.H., W.A.S., N.G.N., and D.P. performed research; D.P. contributed new reagents/analytic tools; K.N.H., W.A.S., N.G.N., K.L.W., C.A.H., P.K.D., and T.B.T. analyzed data; and K.N.H., D.P., and T.B.T. wrote the paper. Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved May 17, 2021 (received for review March 11, 2021) |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.2104809118 |