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| Title | A divergent two-domain structure of the anti-Müllerian hormone prodomain. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 122, Issue 3, Page e2418088122, Year 2025 |
| Publish date | Jan 21, 2025 |
 Authors | James A Howard / Lucija Hok / Richard L Cate / Nathaniel J Sanford / Kaitlin N Hart / Edmund A E Leach / Alena S Bruening / Nicholas Nagykery / Patricia K Donahoe / David Pépin / Thomas B Thompson /  |
| PubMed Abstract | TGFβ 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 ...TGFβ 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 TGFβ family ligand anti-Müllerian 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 TGFβ-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. |
 External links | Proc Natl Acad Sci U S A / PubMed:39805014 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.2 - 3.39 Å |
| Structure data | EMDB-44407, PDB-9ban: EMDB-44408, PDB-9bao: |
| Source |
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 Keywords | SIGNALING PROTEIN/IMMUNE SYSTEM / Complex / TGF-beta prodomain / Signaling ligand / Helical bundle / SIGNALING PROTEIN-IMMUNE SYSTEM complex |
homo sapiens (human)
mus musculus (house mouse)