Identification of a binding site on the type II activin receptor for activin and inhibin
Identification of a binding site on the type II activin receptor for activin and inhibin
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DOI：
10.1074/jbc.275.5.3206
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发表时间：
2000-02-04
影响因子：
4.8
通讯作者：
Vale, W
中科院分区：
文献类型：
--
作者：
Gray, PC;Greenwald, J;Vale, W
II型激活素受体(ActRII和ActRIIB)是一种单跨膜结构域的丝氨酸/苏氨酸激酶受体，能与激活素结合，启动激活素的信号传导和细胞反应，抑制素也能与II型激活素受体结合，拮抗激活素的多种作用。在这里，我们描述了ActRII胞外区的丙氨酸扫描突变，我们鉴定了三个疏水残基(Phe(42)、Trp(60)和Phe(83))的簇，当在全长受体的背景下单独突变为丙氨酸时，导致激活素和抑制素与ActRII结合的中断，每个丙氨酸取代的ActRII突变体保留激活素结合的能力，并支持与激活素形成交联体的能力并支持与I型激活素受体ALK4的活化。与野生型ActRII不同，三个不能结合激活素的突变体在皮质促肾上腺皮质细胞系中瞬时表达时，不会导致激活信号的增加我们的结果表明，这些残基在ActRII上形成了与激活素和抑制素功能相互作用所需的关键结合面，这一首次鉴定的转化生长因子-p家族成员结合位点可能为表征超家族其他成员的结合位点提供一般基础。
Type II activin receptors (ActRII and ActRIIB) are single-transmembrane domain serine/threonine kinase receptors that bind activin to initiate the signaling and cellular responses triggered by this hormone, Inhibin also binds type II activin receptors and antagonizes many activin effects. Here we describe alanine scanning mutagenesis of the ActRII extracellular domain, We identify a cluster of three hydrophobic residues (Phe(42), Trp(60), and phe(83)) that, when individually mutated to alanine in the context of the full-length receptor, cause the disruption of activin and inhibin binding to ActRII, Each of the alanine-substituted ActRII mutants retaining activin binding maintains the ability to form crosslinked complexes with activin and supports activin cross-linking to the type I activin receptor ALK4, Unlike wild-type ActRII, the three mutants unable to bind activin do not cause an increase in activin signaling when transiently expressed in a corticotroph cell line, Together, our results implicate these residues in forming a critical binding surface on ActRII required for functional interactions with both activin and inhibin, This first identification of a transforming growth factor-p family member binding site may provide a general basis for characterizing binding sites for other members of the superfamily.