Functional promiscuity of squirrel monkey growth hormone receptor toward both primate and nonprimate growth hormones.
Functional promiscuity of squirrel monkey growth hormone receptor toward both primate and nonprimate growth hormones.
复制标题
松鼠猴生长激素受体对灵长类和非灵长类生长激素的功能混杂。
DOI：
10.1093/oxfordjournals.molbev.a004166
复制
发表时间：
2002
影响因子：
10.7
通讯作者：
Li,Wen-Hsiung
中科院分区：
文献类型：
--
作者：
Yi,Soojin;Bernat,Bryan;Pál,Gábor;Kossiakoff,Anthony;Li,Wen-Hsiung
灵长类动物生长激素（GH）进化迅速，从推测的祖先真动物序列中经历了约30%的氨基酸替换。然而，人类生长激素（hGH）在非灵长类哺乳动物中是有效的。相反，它的功能对应物，人类生长激素受体（hGHR），已经进化出物种特异性，因此它只对旧大陆灵长类动物的GHs有反应。有人提出，hGHR的这种物种特异性主要是由于在GH的171位发生His→Asp变化后，43位发生了Leu→Arg变化。序列分析支持了这一假设，并揭示了GH:GHR共同进化的过渡阶段仍然存在于新大陆猴中。例如，虽然松鼠猴的GH在171位有His→Asp取代，但其GHR的第43个残基是Leu，即非灵长类残基。如果松鼠猴确实代表了生长激素和GHR共同进化的中间阶段，那么它的GHR应该对生长激素和非灵长类动物的生长激素都有反应。此外，如果物种特异性的出现是选择更有效的GH:GHR相互作用的结果，那么将松鼠猴生长激素受体（smGHR）的残基43改变为Arg应该会增加其对更高灵长类生长激素的结合亲和力。为了验证这些假设，我们使用表面等离子体共振方法进行了smGHR与人和大鼠GHs之间的蛋白质结合测定。此外，我们还测量了人类和松鼠猴ghr 43位互易突变对人类和松鼠猴ghr的结合亲和力。结合动力学分析结果清楚地表明smGHR处于物种特异性进化的中间状态。有趣的是，smGHR 43位残基Arg的改变并没有导致结合亲和力的增加。讨论了这些结果对GH:GHR相互作用演变和功能演变的影响。
Primate growth hormone (GH) has evolved rapidly, having undergone ∼30% amino acid substitutions from the inferred ancestral eutherian sequence. Nevertheless, human growth hormone (hGH) is physiologically effective when administered to nonprimate mammals. In contrast, its functional counterpart, the human growth hormone receptor (hGHR), has evolved species specificity so that it responds only to Old World primate GHs. It has been proposed that this species specificity of the hGHR is largely caused by the Leu → Arg change at position 43 after a prior His → Asp change at position 171 of the GH. Sequence analyses supported this hypothesis and revealed that the transitional phase in the GH:GHR coevolution still persists in New World monkeys. For example, although the GH of the squirrel monkey has the His → Asp substitution at position 171, residue 43 of its GHR is a Leu, the nonprimate residue. If the squirrel monkey truly represents an intermediate stage of GH:GHR coevolution, its GHR should respond to both hGH and nonprimate GH. Also, if the emergence of species specificity was a result of the selection for a more efficient GH:GHR interaction, then changing residue 43 of the squirrel monkey growth hormone receptor (smGHR) to Arg should increase its binding affinity toward higher primate GH. To test these hypotheses, we performed protein-binding assays between the smGHR and both human and rat GHs, using the surface plasmon resonance methodology. Furthermore, the effects of reciprocal mutations at position 43 of human and squirrel monkey GHRs are measured for their binding affinities toward human and squirrel monkey GHs. The results from the binding kinetic assays clearly demonstrate that the smGHR is in the intermediate state of the evolution of species specificity. Interestingly, the altered residue Arg at position 43 of the smGHR does not lead to an increased binding affinity. The implications of these results on the evolution of the GH:GHR interaction and on functional evolution are discussed.