{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T13:10:17Z","timestamp":1776258617421,"version":"3.50.1"},"reference-count":52,"publisher":"The Endocrine Society","issue":"7","license":[{"start":{"date-parts":[[2020,4,25]],"date-time":"2020-04-25T00:00:00Z","timestamp":1587772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["5T32ES007250-30"],"award-info":[{"award-number":["5T32ES007250-30"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1203044"],"award-info":[{"award-number":["OPP1203044"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005294","name":"Massachusetts General Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005294","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ovarian Cancer Research Program","award":["W81XWH-17-1-0212"],"award-info":[{"award-number":["W81XWH-17-1-0212"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Anti-M\u00fcllerian hormone (AMH) or M\u00fcllerian inhibiting substance is a unique member of the TGF-\u03b2 family responsible for development and differentiation of the reproductive system. AMH signals through its own dedicated type II receptor, anti-M\u00fcllerian hormone receptor type II (AMHR2), providing an exclusive ligand-receptor pair within the broader TGF-\u03b2 family. In this study, we used previous structural information to derive a model of AMH bound to AMHR2 to guide mutagenesis studies to identify receptor residues important for AMH signaling. Nonconserved mutations were introduced in AMHR2 and characterized in an AMH-responsive cell-based luciferase assay and native PAGE. Collectively, our results identified several residues important for AMH signaling within the putative ligand binding interface of AMHR2. Our results show that AMH engages AMHR2 at a similar interface to how activin and BMP class ligands bind the type II receptor, ACVR2B; however, there are significant molecular differences at the ligand interface of these 2 receptors, where ACVR2B is mostly hydrophobic and AMHR2 is predominately charged. Overall, this study shows that although the location of ligand binding on the receptor is similar to ACVR2A, ACVR2B, and BMPR2; AMHR2 uses unique ligand-receptor interactions to impart specificity for AMH.<\/jats:p>","DOI":"10.1210\/endocr\/bqaa066","type":"journal-article","created":{"date-parts":[[2020,4,25]],"date-time":"2020-04-25T18:35:52Z","timestamp":1587839752000},"source":"Crossref","is-referenced-by-count":16,"title":["Mutational Analysis of the Putative Anti-M\u00fcllerian Hormone (AMH) Binding Interface on its Type II Receptor, AMHR2"],"prefix":"10.1210","volume":"161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0484-1969","authenticated-orcid":false,"given":"Kaitlin N","family":"Hart","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA"},{"name":"Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-6708","authenticated-orcid":false,"given":"David","family":"P\u00e9pin","sequence":"additional","affiliation":[{"name":"Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"},{"name":"Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Czepnik","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia K","family":"Donahoe","sequence":"additional","affiliation":[{"name":"Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"},{"name":"Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7041-5047","authenticated-orcid":false,"given":"Thomas B","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2020,4,25]]},"reference":[{"issue":"12","key":"2021121822161488200_CIT0001","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/nrg1225","article-title":"Developmental genetics of the female reproductive tract in mammals","volume":"4","author":"Kobayashi","year":"2003","journal-title":"Nat Rev Genet."},{"key":"2021121822161488200_CIT0002","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0070-2153(08)60550-5","article-title":"The in vivo roles of m\u00fcllerian-inhibiting substance","volume":"29","author":"Behringer","year":"1994","journal-title":"Curr Top Dev Biol."},{"issue":"4","key":"2021121822161488200_CIT0003","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1210\/endo-114-4-1315","article-title":"Production of anti-M\u00fcllerian hormone: another homology between Sertoli and granulosa cells","volume":"114","author":"Vigier","year":"1984","journal-title":"Endocrinology."},{"issue":"5627","key":"2021121822161488200_CIT0004","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/269411a0","article-title":"Anti-M\u00fcllerian hormone is a functional marker of foetal Sertoli cells","volume":"269","author":"Tran","year":"1977","journal-title":"Nature."},{"issue":"2","key":"2021121822161488200_CIT0005","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3181\/00379727-66-16071","article-title":"The age factor in the castration of male rabbit fetuses","volume":"66","author":"Jost","year":"1947","journal-title":"Proc Soc Exp Biol Med."},{"issue":"2","key":"2021121822161488200_CIT0006","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1095\/biolreprod35.2.447","article-title":"The ontogeny of mullerian inhibiting substance in granulosa cells of the bovine ovarian follicle","volume":"35","author":"Takahashi","year":"1986","journal-title":"Biol Reprod."},{"issue":"2","key":"2021121822161488200_CIT0007","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1093\/molehr\/gah015","article-title":"Anti-M\u00fcllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment","volume":"10","author":"Weenen","year":"2004","journal-title":"Mol Hum Reprod."},{"issue":"10","key":"2021121822161488200_CIT0008","first-page":"1636","article-title":"The anti mullerian hormone- a novel marker for assessing the ovarian reserve in women with regular menstrual cycles","volume":"6","author":"Kalaiselvi","year":"2012","journal-title":"J Clin Diagn Res."},{"issue":"2","key":"2021121822161488200_CIT0009","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ajog.2017.02.027","article-title":"Ovarian reserve testing: a user\u2019s guide","volume":"217","author":"Tal","year":"2017","journal-title":"Am J Obstet Gynecol."},{"issue":"4","key":"2021121822161488200_CIT0010","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1093\/humupd\/dmi014","article-title":"AMH and AMH receptor defects in persistent M\u00fcllerian duct syndrome","volume":"11","author":"Josso","year":"2005","journal-title":"Hum Reprod Update."},{"issue":"9","key":"2021121822161488200_CIT0011","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1093\/hmg\/5.9.1269","article-title":"A 27 base-pair deletion of the anti-m\u00fcllerian type II receptor gene is the most common cause of the persistent m\u00fcllerian duct syndrome","volume":"5","author":"Imbeaud","year":"1996","journal-title":"Hum Mol Genet."},{"issue":"3","key":"2021121822161488200_CIT0012","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1159\/000475516","article-title":"The persistent M\u00fcllerian duct syndrome: an update based upon a personal experience of 157 Cases","volume":"11","author":"Picard","year":"2017","journal-title":"Sex Dev."},{"issue":"8","key":"2021121822161488200_CIT0013","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1210\/jc.2017-00612","article-title":"Pathogenic anti-M\u00fcllerian hormone variants in polycystic ovary syndrome","volume":"102","author":"Gorsic","year":"2017","journal-title":"J Clin Endocrinol Metab."},{"issue":"7","key":"2021121822161488200_CIT0014","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1210\/jc.2018-02178","article-title":"Functional genetic variation in the anti-M\u00fcllerian hormone pathway in women with polycystic ovary syndrome","volume":"104","author":"Gorsic","year":"2019","journal-title":"J Clin Endocrinol Metab."},{"key":"2021121822161488200_CIT0015","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s12958-015-0134-9","article-title":"Role of Anti-M\u00fcllerian hormone in pathophysiology, diagnosis and treatment of polycystic ovary syndrome: a review","volume":"13","author":"Dumont","year":"2015","journal-title":"Reprod Biol Endocrinol."},{"issue":"10","key":"2021121822161488200_CIT0016","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.15537\/smj.2018.10.23413","article-title":"Can we use serum anti-Mullerian hormone to differentiate the diagnosis between polycystic ovary syndrome patients and healthy women with polycystic ovarian morphology and regular menstrual cycles","volume":"39","author":"Aydo\u011fmu\u015f","year":"2018","journal-title":"Saudi Med J."},{"issue":"8","key":"2021121822161488200_CIT0017","doi-asserted-by":"crossref","first-page":"3332","DOI":"10.1210\/jc.2013-1393","article-title":"Can anti-Mullerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and meta-analysis of extracted data","volume":"98","author":"Iliodromiti","year":"2013","journal-title":"J Clin Endocrinol Metab."},{"issue":"6","key":"2021121822161488200_CIT0018","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41591-018-0035-5","article-title":"Elevated prenatal anti-M\u00fcllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood","volume":"24","author":"Tata","year":"2018","journal-title":"Nature Medicine."},{"issue":"5","key":"2021121822161488200_CIT0019","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/0092-8674(86)90783-X","article-title":"Isolation of the bovine and human genes for M\u00fcllerian inhibiting substance and expression of the human gene in animal cells","volume":"45","author":"Cate","year":"1986","journal-title":"Cell."},{"key":"2021121822161488200_CIT0020","first-page":";8(12):a022103.","article-title":"Structural biology and evolution of the TGF-\u03b2 family","author":"Hinck","year":"2016","journal-title":"Cold Spring Harb Perspect Biol."},{"key":"2021121822161488200_CIT0021","first-page":";244(17):1530-1546","article-title":"Structural biology of the TGF\u03b2 family","author":"Goebel","year":"2019","journal-title":"Exp Biol Med (Maywood)."},{"issue":"6","key":"2021121822161488200_CIT0022","first-page":"936","article-title":"The serine\/threonine transmembrane receptor ALK2 mediates M\u00fcllerian inhibiting substance signaling","volume":"15","author":"Visser","year":"2001","journal-title":"Mol Endocrinol."},{"issue":"6","key":"2021121822161488200_CIT0023","first-page":"946","article-title":"M\u00fcllerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression","volume":"15","author":"Clarke","year":"2001","journal-title":"Mol Endocrinol."},{"issue":"36","key":"2021121822161488200_CIT0024","doi-asserted-by":"crossref","first-page":"27973","DOI":"10.1074\/jbc.M002704200","article-title":"Engagement of bone morphogenetic protein type IB receptor and Smad1 signaling by anti-M\u00fcllerian hormone and its type II receptor","volume":"275","author":"Gou\u00e9dard","year":"2000","journal-title":"J Biol Chem."},{"issue":"31","key":"2021121822161488200_CIT0025","doi-asserted-by":"crossref","first-page":"4984","DOI":"10.1038\/sj.onc.1208686","article-title":"Role of type I receptors for anti-M\u00fcllerian hormone in the SMAT-1 Sertoli cell line","volume":"24","author":"Belville","year":"2005","journal-title":"Oncogene."},{"issue":"7","key":"2021121822161488200_CIT0026","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1093\/emboj\/cdg156","article-title":"Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions","volume":"22","author":"Thompson","year":"2003","journal-title":"Embo J."},{"issue":"31","key":"2021121822161488200_CIT0027","doi-asserted-by":"crossref","first-page":"15505","DOI":"10.1073\/pnas.1906253116","article-title":"Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity","volume":"116","author":"Goebel","year":"2019","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"3","key":"2021121822161488200_CIT0028","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.molcel.2004.07.011","article-title":"A flexible activin explains the membrane-dependent cooperative assembly of TGF-beta family receptors","volume":"15","author":"Greenwald","year":"2004","journal-title":"Mol Cell."},{"issue":"3","key":"2021121822161488200_CIT0029","first-page":"203","article-title":"Crystal structure of the human TbetaR2 ectodomain\u2013TGF-beta3 complex","volume":"9","author":"Hart","year":"2002","journal-title":"Nat Struct Biol."},{"issue":"11","key":"2021121822161488200_CIT0030","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1210\/me.2010-0273","article-title":"Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta","volume":"24","author":"di Clemente","year":"2010","journal-title":"Mol Endocrinol."},{"issue":"Pt 3","key":"2021121822161488200_CIT0031","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1042\/bj20031961","article-title":"The anti-M\u00fcllerian hormone type II receptor: insights into the binding domains recognized by a monoclonal antibody and the natural ligand","volume":"379","author":"Salhi","year":"2004","journal-title":"Biochem J."},{"issue":"1","key":"2021121822161488200_CIT0032","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1002\/pro.3290","article-title":"Clustal Omega for making accurate alignments of many protein sequences","volume":"27","author":"Sievers","year":"2018","journal-title":"Protein Sci."},{"issue":"4","key":"2021121822161488200_CIT0033","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1002\/prot.20176","article-title":"Accurate prediction of solvent accessibility using neural networks-based regression","volume":"56","author":"Adamczak","year":"2004","journal-title":"Proteins."},{"key":"2021121822161488200_CIT0034"},{"issue":"Web Server issue","key":"2021121822161488200_CIT0035","doi-asserted-by":"crossref","first-page":"W252","DOI":"10.1093\/nar\/gku340","article-title":"SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information","volume":"42","author":"Biasini","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2021121822161488200_CIT0036"},{"issue":"2","key":"2021121822161488200_CIT0037","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0092-8674(00)81561-5","article-title":"OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways","volume":"100","author":"Hata","year":"2000","journal-title":"Cell."},{"issue":"9","key":"2021121822161488200_CIT0038","doi-asserted-by":"crossref","first-page":"E1688","DOI":"10.1073\/pnas.1620729114","article-title":"AMH\/MIS as a contraceptive that protects the ovarian reserve during chemotherapy","volume":"114","author":"Kano","year":"2017","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"1","key":"2021121822161488200_CIT0039","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1142\/S2339547813500076","article-title":"An albumin leader sequence coupled with a cleavage site modification enhances the yield of recombinant C-terminal Mullerian Inhibiting Substance","volume":"1","author":"P\u00e9pin","year":"2013","journal-title":"Technology."},{"key":"2021121822161488200_CIT0040"},{"key":"2021121822161488200_CIT0041"},{"key":"2021121822161488200_CIT0042"},{"issue":"16","key":"2021121822161488200_CIT0043","doi-asserted-by":"crossref","first-page":"6333","DOI":"10.1074\/jbc.RA118.005831","article-title":"Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11","volume":"294","author":"McCoy","year":"2019","journal-title":"J Biol Chem."},{"issue":"W1","key":"2021121822161488200_CIT0044","doi-asserted-by":"crossref","first-page":"W314","DOI":"10.1093\/nar\/gkv314","article-title":"Stock-based detection of protein oligomeric states in jsPISA","volume":"43","author":"Krissinel","year":"2015","journal-title":"Nucleic Acids Res."},{"issue":"12","key":"2021121822161488200_CIT0045","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/j.febslet.2013.04.014","article-title":"The type 2 anti-M\u00fcllerian hormone receptor has splice variants that are dominant-negative inhibitors","volume":"587","author":"Imhoff","year":"2013","journal-title":"FEBS Lett."},{"issue":"7","key":"2021121822161488200_CIT0046","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/mrd.22828","article-title":"Anti-M\u00fcllerian hormone signaling is influenced by Follistatin 288, but not 14 other transforming growth factor beta superfamily regulators","volume":"84","author":"Kawagishi","year":"2017","journal-title":"Mol Reprod Dev."},{"issue":"1","key":"2021121822161488200_CIT0047","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ab.2005.10.030","article-title":"An assay for the determination of biologically active bone morphogenetic proteins using cells transfected with an inhibitor of differentiation promoter-luciferase construct","volume":"349","author":"Logeart-Avramoglou","year":"2006","journal-title":"Anal Biochem."},{"issue":"5","key":"2021121822161488200_CIT0048","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.jmb.2012.10.003","article-title":"Members of the DAN family are BMP antagonists that form highly stable noncovalent dimers","volume":"424","author":"Kattamuri","year":"2012","journal-title":"J Mol Biol."},{"issue":"2","key":"2021121822161488200_CIT0049","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1074\/jbc.M111.270801","article-title":"Structure of myostatin\u00b7follistatin-like 3: N-terminal domains of follistatin-type molecules exhibit alternate modes of binding","volume":"287","author":"Cash","year":"2012","journal-title":"J Biol Chem."},{"issue":"7","key":"2021121822161488200_CIT0050","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1177\/1087057113482585","article-title":"Development of a small-molecule screening method for inhibitors of cellular response to myostatin and activin A","volume":"18","author":"Cash","year":"2013","journal-title":"J Biomol Screen."},{"issue":"5","key":"2021121822161488200_CIT0051","doi-asserted-by":"crossref","first-page":"E866","DOI":"10.1073\/pnas.1714622115","article-title":"Molecular characterization of latent GDF8 reveals mechanisms of activation","volume":"115","author":"Walker","year":"2018","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"9","key":"2021121822161488200_CIT0052","doi-asserted-by":"crossref","first-page":"3125","DOI":"10.1074\/jbc.RA118.006817","article-title":"High-throughput screens for agonists of bone morphogenetic protein (BMP) signaling identify potent benzoxazole compounds","volume":"294","author":"Bradford","year":"2019","journal-title":"J Biol Chem."}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqaa066\/33128696\/bqaa066.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/161\/7\/bqaa066\/41814882\/endo_161_7_bqaa066.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/161\/7\/bqaa066\/41814882\/endo_161_7_bqaa066.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T22:17:32Z","timestamp":1639865852000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqaa066\/5825248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,25]]},"references-count":52,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2020,7,1]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqaa066","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,7]]},"published":{"date-parts":[[2020,4,25]]},"article-number":"bqaa066"}}