ZINC MEDIATION OF THE BINDING OF HUMAN GROWTH-HORMONE TO THE HUMAN PROLACTIN RECEPTOR
ZINC MEDIATION OF THE BINDING OF HUMAN GROWTH-HORMONE TO THE HUMAN PROLACTIN RECEPTOR
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DOI：
10.1126/science.2270485
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发表时间：
1990-12-21
期刊：
影响因子：
56.9
通讯作者：
WELLS, JA
中科院分区：
文献类型：
--
作者：
CUNNINGHAM, BC;BASS, S;WELLS, JA
人类生长激素（hGH）引起多种生物活性，包括与催乳素（PRL）受体结合而产生的泌乳。添加50微摩尔ZnCl2后，hGH对hPRL受体胞外结合域（hPRLbp）的结合亲和力提高了约8000倍。hGH与hGH结合蛋白（hGHbp）或hPRL与hPRLbp的结合不需要锌。生理浓度下的其他二价金属离子（Ca2+, Mg2+, Cu2+， Mn2+和Co2+）不支持这种强结合。Scatchard分析表明，每个hGH.cntdot.hPRLbp络合物的化学计量量为1个Zn2+。突变分析表明，hPRLbp（在所有PRL受体中保守，但在GH受体中不保守）中hGH和His188中的三个残基（His18、His21和Glu174）簇可能是Zn2+配体。这种多肽激素受体“锌三明治”提供了一种分子机制来解释为什么非灵长类动物GHs不是乳源性的，并提供了锌缺乏与hGH功能改变之间的分子联系。
Human growth hormone (hGH) elicits a diverse set of biological activities including lactation that derives from binding to the prolactin (PRL) receptor. The binding affinity of hGH for the extracellular binding domain of the hPRL receptor (hPRLbp) was increased about 8000-fold by addition of 50 micromolar ZnCl2. Zinc was not required for binding of hGH to the hGH binding protein (hGHbp) or for binding of hPRL to the hPRLbp. Other divalent metal ions (Ca2+, Mg2+, Cu2+, Mn2+, and Co2+) at physiological concentrations did not support such strong binding. Scatchard analysis indicated a stoichiometry of one Zn2+ per hGH.cntdot.hPRLbp complex. Mutational analysis showed that a cluster of three residues (His18, His21, and Glu174) in hGH and His188 from the hPRLbp (conserved in all PRL receptors but not GH receptors) are probable Zn2+ ligands. This polypeptide hormone.cntdot.receptor "zinc sandwich" provides a molecular mechanism to explain why nonprimate GHs are not lactogenic and offers a molecular link between zinc deficiency and its association with altered functions of hGH.