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From Proteopedia
The Anti-Mullerian Hormone prodomain in complex with the growth factor and 6E11 Fab in C1 symmetry
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:34155118, PubMed:3754790, 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 PubMedTGFbeta family ligands are synthesized as precursors consisting of an N-terminal prodomain and C-terminal growth factor (GF) signaling domain. After proteolytic processing, the prodomain typically remains noncovalently associated with the GF, sometimes forming a high-affinity latent procomplex that requires activation. For the TGFbeta family ligand anti-Mullerian hormone (AMH), the prodomain maintains a high-affinity interaction with its GF that does not render it latent. While the prodomain can be displaced by the type II receptor, AMHR2, the nature of the GF:prodomain interaction and the mechanism of prodomain displacement by AMHR2 are currently unknown. We show here that the AMH prodomain exhibits an atypical two-domain structure, containing a dimerizing and a GF-binding domain connected through a flexible linker. Cryo-EM and genomic analyses show that the distinctive GF-binding domain, the result of an exon insertion 450 Mya, comprises a helical bundle and a belt-like structure which interact with the GF at the type II and I receptor binding sites, respectively. The dimerizing domain, which adopts a TGFbeta-like propeptide fold, covalently connects two prodomains through intermolecular disulfide bonds. Disease mutations map to both the GF-binding and dimerization domains. Our results support a model where AMHR2 displaces the helical bundle and induces a conformational change in the GF, followed by release of the prodomain and engagement of the type I receptor. Collectively, this study shows that the AMH prodomain has evolved an atypical binding interaction with the GF that favors, without disrupting signaling, the maintenance of a noncovalent complex until receptors are engaged. A divergent two-domain structure of the anti-Mullerian hormone prodomain.,Howard JA, Hok L, Cate RL, Sanford NJ, Hart KN, Leach EAE, Bruening AS, Nagykery N, Donahoe PK, Pepin D, Thompson TB Proc Natl Acad Sci U S A. 2025 Jan 21;122(3):e2418088122. doi: , 10.1073/pnas.2418088122. Epub 2025 Jan 13. PMID:39805014[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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