Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family.
Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family.
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DOI：
10.1073/pnas.2104809118
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发表时间：
2021-06-29
影响因子：
11.1
通讯作者：
Thompson TB
中科院分区：
文献类型：
--
作者：
Hart KN;Stocker WA;Nagykery NG;Walton KL;Harrison CA;Donahoe PK;Pépin D;Thompson TB
抗苗勒氏激素(AMH)在男性性别分化和女性生殖发育中起着至关重要的作用。因此，AMH被广泛用作测量女性生育能力、估计更年期开始的生物标志物，并与多囊卵巢综合征和卵巢早衰等生殖综合征有关。尽管AMH与生物学相关，但它如何在分子水平上发挥作用尚不清楚。在这项研究中，我们证明AMH与其受体AMHR2结合，使用与其他类型II受体不同的广泛接口。此外，我们确定了AMH和AMHR2中负责特异性和AMH信号转导所必需的几个区域。抗苗勒氏激素(AMH)，或苗勒氏抑制物质，是一种蛋白质类激素，在男性胎儿性别分化和女性卵泡发生调节过程中促进苗勒氏管退行性。AMH是转化生长因子-β(TGFR-β)家族中的一员，该家族已进化为通过其专用的II型受体-AMHR2(AMHR2)来传递信号。其他转化生长因子-β家族成员的结构揭示了配体如何推断其同源受体的特异性；然而，AMH如何在分子水平上与AMHR2结合尚不清楚。因此，在这项研究中，我们解决了AMH与AMHR2胞外结构域结合的X射线晶体结构，分辨率为2.6ó。结构表明，虽然AMH与AMHR2结合的位置与激活素和BMP配体与其II型受体结合的位置相似，但AMH和AMHR2的差异导致了高度特异性的相互作用。此外，利用基于AMH响应细胞的荧光素酶分析，我们发现AMHR2的手指1的构象和AMH上的K534形成的盐桥和AMHR2的D81/E84是AMH/AMHR2相互作用的关键。总体而言，我们的研究强调了AMH如何使用通过修改AMHR2的三指毒素折叠而促进的受体结合的修改范例来与AMHR2结合。此外，了解这些有助于结合特异性的因素将有助于激动剂或拮抗剂的设计或抗体疗法的选择。
Anti-Müllerian hormone (AMH) plays a crucial role in male sex differentiation and female reproductive development. As such, AMH is widely used as a biomarker for measuring a woman’s fertility, estimating onset of menopause, and has been implicated in reproductive syndromes such as polycystic ovarian syndrome and premature ovarian failure. Despite its biological relevance, how AMH functions on the molecular level is not well understood. In this study, we show that AMH engages its receptor, AMHR2, using an extensive interface distinct from other type II receptors. Furthermore, we identify several regions in both AMH and AMHR2 that are responsible for specificity and required for AMH signaling. Anti-Müllerian hormone (AMH), or Müllerian-inhibiting substance, is a protein hormone that promotes Müllerian duct regression during male fetal sexual differentiation and regulation of folliculogenesis in women. AMH is a member of the transforming growth factor beta (TGF-β) family, which has evolved to signal through its own dedicated type II receptor, AMH receptor type II (AMHR2). Structures of other TGF-β 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 2.6Å. 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.
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影响因子：
7.2
作者：
Hinck AP;Mueller TD;Springer TA
通讯作者：
Springer TA
DOI：
10.1073/pnas.0602558103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Allendorph, George P.;Vale, Wylie W.;Choe, Senyon
通讯作者：
Choe, Senyon
DOI：
10.1073/pnas.1906253116
发表时间：
2019-07-30
影响因子：
11.1
作者：
Goebel, Erich J.;Corpina, Richard A.;Thompson, Thomas B.
通讯作者：
Thompson, Thomas B.
影响因子：
5.7
作者：
Boesen, CC;Radaev, S;Sun, PD
通讯作者：
Sun, PD
影响因子：
4.8
作者：
Hart, Kaitlin N.;Pepin, David;Thompson, Thomas B.
通讯作者：
Thompson, Thomas B.