Common structural requirements for heptahelical domain function in class A and class C G protein-coupled receptors
Common structural requirements for heptahelical domain function in class A and class C G protein-coupled receptors
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DOI：
10.1074/jbc.m611071200
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发表时间：
2007-04-20
影响因子：
4.8
通讯作者：
Prezeau, Laurent
中科院分区：
文献类型：
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作者：
Binet, Virginie;Duthey, Beatrice;Prezeau, Laurent
G蛋白偶联受体（GPCR）是细胞通讯的关键参与者。已经鉴定了几类这样的受体。虽然所有的GPCR都具有直接激活G蛋白的七螺旋结构域，但不同类别的受体内的重要结构和序列差异表明了不同的激活机制。在这里，我们表明，高度保守的带电残基可能参与跨膜结构域（TM）3和6之间的相互作用网络在细胞质侧的C类GPCR的γ-氨基丁酸B型受体的激活是至关重要的。实际上，由γ-氨基丁酸B-2型的TM 3中保守的赖氨酸残基突变成天冬氨酸或谷氨酸而导致的功能丧失可以通过将TM 6的保守的酸性残基突变成赖氨酸或精氨酸而部分地挽救。此外，保守的赖氨酸突变成酸性残基导致显示高激动剂亲和力的非功能性受体。这让人想起类似的离子网络，其构成稳定许多A类视紫红质样GPCR的非活性状态的锁。这些数据表明，尽管它们的原始结构，C类GPCR与A类受体共享至少一些控制G蛋白活化的共同结构特征。
Gprotein-coupled receptors (GPCRs) are key players in cell communication. Several classes of such receptors have been identified. Although all GPCRs possess a heptahelical domain directly activating G proteins, important structural and sequence differences within receptors from different classes suggested distinct activation mechanisms. Here we show that highly conserved charged residues likely involved in an interaction network between transmembrane domains (TM) 3 and 6 at the cytoplasmic side of class C GPCRs are critical for activation of the gamma-aminobutyric acid type B receptor. Indeed, the loss of function resulting from the mutation of the conserved lysine residue into aspartate or glutamate in the TM3 of gamma-aminobutyric acid type B-2 can be partly rescued by mutating the conserved acidic residue of TM6 into either lysine or arginine. In addition, mutation of the conserved lysine into an acidic residue leads to a nonfunctional receptor that displays a high agonist affinity. This is reminiscent of a similar ionic network that constitutes a lock stabilizing the inactive state of many class A rhodopsin-like GPCRs. These data reveal that despite their original structure, class C GPCRs share with class A receptors at least some common structural feature controlling G protein activation.