7l0j | pdb_00007l0j

Structure of AMH bound to AMHR2-ECD

Structural highlights

7l0j is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	NAG, SO4
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:3754790, PubMed:34155118, 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

Anti-Mullerian hormone (AMH), or Mullerian-inhibiting substance, is a protein hormone that promotes Mullerian duct regression during male fetal sexual differentiation and regulation of folliculogenesis in women. AMH is a member of the transforming growth factor beta (TGF-beta) family, which has evolved to signal through its own dedicated type II receptor, AMH receptor type II (AMHR2). Structures of other TGF-beta family members have revealed how ligands infer specificity for their cognate receptors; however, it is unknown how AMH binds AMHR2 at the molecular level. Therefore, in this study, we solved the X-ray crystal structure of AMH bound to the extracellular domain of AMHR2 to a resolution of 2.6A. The structure reveals that while AMH binds AMHR2 in a similar location to Activin and BMP ligand binding to their type II receptors, differences in both AMH and AMHR2 account for a highly specific interaction. Furthermore, using an AMH responsive cell-based luciferase assay, we show that a conformation in finger 1 of AMHR2 and a salt bridge formed by K534 on AMH and D81/E84 of AMHR2 are key to the AMH/AMHR2 interaction. Overall, our study highlights how AMH engages AMHR2 using a modified paradigm of receptor binding facilitated by modifications to the three-finger toxin fold of AMHR2. Furthermore, understanding these elements contributing to the specificity of binding will help in the design of agonists or antagonists or the selection of antibody therapies.

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

Proteopedia Page Contributors and Editors (what is this?)

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] 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

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7l0j | pdb_00007l0j

Structure of AMH bound to AMHR2-ECD

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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