Structural Basis of Non-Latent Signaling by the Anti-Müllerian Hormone Procomplex

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Endocrinology

Background:

• Transforming Growth Factor-beta (TGFβ) family ligands typically form procomplexes with prodomains that regulate their activity.
• Anti-Müllerian Hormone (AMH) is unique, with its prodomain maintaining high affinity for the growth factor (GF) while allowing activity.

Approach:

• Utilized single particle electron microscopy (EM) to determine the structure of the AMH procomplex.
• Analyzed the structural interplay between the AMH prodomain, growth factor, and receptor binding sites.

Key Points:

• The AMH prodomain comprises a TGFβ-like fold and a novel helical bundle GF-binding domain, formed via an ancient exon insertion.
• This GF-binding domain interacts with receptor epitopes.
• The prodomain binding induces a strained, open conformation in the AMH GF.

Conclusions:

• Bivalent binding to AMH receptor 2 (AMHR2) triggers a conformational shift, displacing the prodomain.
• This displacement mechanism is crucial for initiating AMH signaling, distinct from other TGFβ ligands.