Identification of a binding site on the type II activin receptor for activin and inhibin

被引:90
作者
Gray, PC
Greenwald, J
Blount, AL
Kunitake, KS
Donaldson, CJ
Choe, S
Vale, W
机构
[1] Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, La Jolla, CA 92037 USA
[2] Salk Inst Biol Studies, Struct Biol Lab, La Jolla, CA 92037 USA
关键词
D O I
10.1074/jbc.275.5.3206
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:3206 / 3212
页数:7
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