A divergent two- domain structure of the anti- Müllerian hormone prodomain

• 成果类型: Article
• 署名作者: Howard, James A.; Hok, Lucija; Cate, Richard L.; Sanford, Nathaniel J.; Hart, Kaitlin N.; Leach, Edmund A. E.; Bruening, Alena S.; Nagykery, Nicholas; Donahoe, Patricia K.; Thompson, Thomas B.
• 署名单位: University System of Ohio; University of Cincinnati; University System of Ohio; University of Cincinnati; Boston University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9933
• DOI: 10.1073/pnas.2418088122
• 发表日期: 2025-01-21
• 关键词: mullerian-inhibiting substance; duct syndrome; latent gdf8; tgf-beta; precursor; receptor; immunoassay; activation; mechanisms; expression

摘要

TGFf3 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 TGFf3 family ligand anti- M & uuml;llerian 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 TGFf3-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.