9bao | pdb_00009bao

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

Structural highlights

9bao is a 8 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.2Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MIS_HUMAN Persistent Muellerian duct syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

MIS_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 PubMed

TGFbeta 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

↑ Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, Kramer P, Fauser BC, Themmen AP. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004 Feb;10(2):77-83. PMID:14742691 doi:10.1093/molehr/gah015
↑ di Clemente N, Jamin SP, Lugovskoy A, Carmillo P, Ehrenfels C, Picard JY, Whitty A, Josso N, Pepinsky RB, Cate RL. Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta. Mol Endocrinol. 2010 Nov;24(11):2193-206. PMID:20861221 doi:10.1210/me.2010-0273
↑ Hart KN, Stocker WA, Nagykery NG, Walton KL, Harrison CA, Donahoe PK, Pépin D, Thompson TB. Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family. Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2104809118. PMID:34155118 doi:10.1073/pnas.2104809118
↑ Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, Cheung A, Ninfa EG, Frey AZ, Gash DJ, Chow EP, et al.. Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells. Cell. 1986 Jun 6;45(5):685-98. PMID:3754790 doi:10.1016/0092-8674(86)90783-x
↑ Wilson CA, di Clemente N, Ehrenfels C, Pepinsky RB, Josso N, Vigier B, Cate RL. Mullerian inhibiting substance requires its N-terminal domain for maintenance of biological activity, a novel finding within the transforming growth factor-beta superfamily. Mol Endocrinol. 1993 Feb;7(2):247-57. PMID:8469238 doi:10.1210/mend.7.2.8469238
↑ Howard JA, Hok L, Cate RL, Sanford NJ, Hart KN, Leach EAE, Bruening AS, Nagykery N, Donahoe PK, Pépin D, Thompson TB. A divergent two-domain structure of the anti-Müllerian hormone prodomain. Proc Natl Acad Sci U S A. 2025 Jan 21;122(3):e2418088122. PMID:39805014 doi:10.1073/pnas.2418088122

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OCA

[1] Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, Kramer P, Fauser BC, Themmen AP. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004 Feb;10(2):77-83. PMID:14742691 doi:10.1093/molehr/gah015

[2] Clemente N, Jamin SP, Lugovskoy A, Carmillo P, Ehrenfels C, Picard JY, Whitty A, Josso N, Pepinsky RB, Cate RL. Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta. Mol Endocrinol. 2010 Nov;24(11):2193-206. PMID:20861221 doi:10.1210/me.2010-0273

[3] Hart KN, Stocker WA, Nagykery NG, Walton KL, Harrison CA, Donahoe PK, Pépin D, Thompson TB. Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family. Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2104809118. PMID:34155118 doi:10.1073/pnas.2104809118

[4] Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, Cheung A, Ninfa EG, Frey AZ, Gash DJ, Chow EP, et al.. Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells. Cell. 1986 Jun 6;45(5):685-98. PMID:3754790 doi:10.1016/0092-8674(86)90783-x

[5] Wilson CA, di Clemente N, Ehrenfels C, Pepinsky RB, Josso N, Vigier B, Cate RL. Mullerian inhibiting substance requires its N-terminal domain for maintenance of biological activity, a novel finding within the transforming growth factor-beta superfamily. Mol Endocrinol. 1993 Feb;7(2):247-57. PMID:8469238 doi:10.1210/mend.7.2.8469238

[6] Howard JA, Hok L, Cate RL, Sanford NJ, Hart KN, Leach EAE, Bruening AS, Nagykery N, Donahoe PK, Pépin D, Thompson TB. A divergent two-domain structure of the anti-Müllerian hormone prodomain. Proc Natl Acad Sci U S A. 2025 Jan 21;122(3):e2418088122. PMID:39805014 doi:10.1073/pnas.2418088122

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9bao | pdb_00009bao

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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