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Science 21 December 1990:
Vol. 250. no. 4988, pp. 1709 - 1712
DOI: 10.1126/science.2270485
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Articles

Science, Vol 250, Issue 4988, 1709-1712
Copyright © 1990 by American Association for the Advancement of Science

articles

Zinc mediation of the binding of human growth hormone to the human prolactin receptor

BC Cunningham, S Bass, G Fuh, and JA Wells

Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080.

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.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.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.


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