7l0j
From Proteopedia
Structure of AMH bound to AMHR2-ECD
Structural highlights
DiseaseMIS_HUMAN Persistent Muellerian duct syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionMIS_HUMAN Plays an important role in several reproductive functions. Induces Muellerian duct regression during male fetal sexual differentiation (PubMed:3754790, PubMed:34155118, PubMed:8469238). Also plays a role in Leydig cell differentiation and function (By similarity). In female acts as a negative regulator of the primordial to primary follicle transition and decreases FSH sensitivity of growing follicles (PubMed:14742691). AMH signals by binding to a specific type-II receptor, AMHR2, that heterodimerizes with type-I receptors (ACVR1 and BMPR1A), and recruiting SMAD proteins that are translocated to the nucleus to regulate target gene expression (PubMed:20861221, PubMed:34155118).[UniProtKB:P27106][1] [2] [3] [4] [5] Publication Abstract from PubMedAnti-Mullerian hormone (AMH), or Mullerian-inhibiting substance, is a protein hormone that promotes Mullerian duct regression during male fetal sexual differentiation and regulation of folliculogenesis in women. AMH is a member of the transforming growth factor beta (TGF-beta) family, which has evolved to signal through its own dedicated type II receptor, AMH receptor type II (AMHR2). Structures of other TGF-beta 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 2.6A. 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 how AMH 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. Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-beta family.,Hart KN, Stocker WA, Nagykery NG, Walton KL, Harrison CA, Donahoe PK, Pepin D, Thompson TB Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2104809118. doi: , 10.1073/pnas.2104809118. PMID:34155118[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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