9BAO

The Anti-Mullerian Hormone prodomain in complex with the growth factor and 6E11 Fab in C2 symmetry

Summary for 9BAO

• Entry DOI: 10.2210/pdb9bao/pdb
• EMDB information: 44408
• Descriptor: Muellerian-inhibiting factor, 6E11 Antibody IgG2A Heavy Chain, 6E11 Antibody kappa Light Chain, ... (4 entities in total)
• Functional Keywords: complex, tgf-beta prodomain, signaling ligand, helical bundle, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 209112.41

Authors

Howard, J.A.,Thompson, T.B. (deposition date: 2024-04-04, release date: 2025-01-29)

Primary citation

Howard, J.A.,Hok, L.,Cate, R.L.,Sanford, N.J.,Hart, K.N.,Leach, E.A.E.,Bruening, A.S.,Nagykery, N.,Donahoe, P.K.,Pepin, D.,Thompson, T.B.
A divergent two-domain structure of the anti-Mullerian hormone prodomain.
Proc.Natl.Acad.Sci.USA, 122:e2418088122-e2418088122, 2025

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 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.

PubMed: 39805014
DOI: 10.1073/pnas.2418088122

Experimental method

ELECTRON MICROSCOPY (3.2 Å)