Structural Basis of Non-Latent Signaling by the Anti-Müllerian Hormone Procomplex.
Structural Basis of Non-Latent Signaling by the Anti-Müllerian Hormone Procomplex.
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抗苗勒管激素原复合物非潜在信号传导的结构基础。
DOI：
10.1101/2024.04.01.587627
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Thompson,ThomasB
中科院分区：
文献类型：
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作者：
Howard,JamesA;Hok,Lucija;Cate,RichardL;Sanford,NathanielJ;Hart,KaitlinN;Leach,EdmundAe;Bruening,AlenaS;Pépin,David;Donahoe,PatriciaK;Thompson,ThomasB
大多数 TGFβ 家族配体以前复合物形式存在，由与生长因子 (GF) 非共价结合的前结构域组成；虽然一些前结构域具有潜伏期，但抗苗勒氏管激素 (AMH) 前结构域对 GF 保持非常高的亲和力，但仍保持活性。使用单粒子 EM 方法，我们显示 AMH 前结构域由两个子结构域组成：一个残留的 TGFβ 前结构域样折叠和一个新颖的螺旋束 GF 结合结构域，这是 4.5 亿年前外显子插入的结果，与两个受体表位结合。当与前结构域结合时，AMH GF 扭曲成一种紧张的开放构象，其在 AMHR2 二价结合后关闭，通过构象转变机制取代前结构域以允许信号传导。
Most TGFβ family ligands exist as procomplexes consisting of a prodomain noncovalently bound to a growth factor (GF); Whereas some prodomains confer latency, the Anti-Müllerian Hormone (AMH) prodomain maintains a remarkably high affinity for the GF yet remains active. Using single particle EM methods, we show the AMH prodomain consists of two subdomains: a vestigial TGFβ prodomain-like fold and a novel, helical bundle GF-binding domain, the result of an exon insertion 450 million years ago, that engages both receptor epitopes. When associated with the prodomain, the AMH GF is distorted into a strained, open conformation whose closure upon bivalent binding of AMHR2 displaces the prodomain through a conformational shift mechanism to allow for signaling.