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J. Biol. Chem., Vol. 279, Issue 43, 44775-44784, October 22, 2004

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Increased Site 1 Affinity Improves Biopotency of Porcine Growth Hormone

EVIDENCE AGAINST DIFFUSION DEPENDENT RECEPTOR DIMERIZATION^*

Yu Wan, Andrew McDevitt, Bojiang Shen, Mark L. Smythe, and Michael J. Waters

From the Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, St. Lucia 4072, Australia

Based on phage display optimization studies with human growth hormone (GH), it is thought that the biopotency of GH cannot be increased. This is proposed to be a result of the affinity of the first receptor for hormone far exceeding that which is required to trap the hormone long enough to allow diffusion of the second receptor to form the ternary complex, which initiates signaling. We report here that despite similar site 1 kinetics to the hGH/hGH receptor interaction, the potency of porcine GH for its receptor can be increased up to 5-fold by substituting hGH residues involved in site 1 binding into pGH. Based on extensive mutations and BIAcore studies, we show that the higher potency and site 1 affinity of hGH for the pGHR is primarily a result of a decreased off-rate associated with residues in the extended loop between helices 1 and 2 that interact with the two key tryptophans Trp¹⁰⁴ and Trp¹⁶⁹ in the receptor binding hot spot. Our mutagenic analysis has also identified a second determinant (Lys¹⁶⁵), which in addition to His¹⁶⁹, restricts the ability of non-primate hormones to activate hGH receptor. The increased biopotency of GH that we observe can be explained by a model for GH receptor activation where subunit alignment is critical for effective signaling.

Received for publication, June 2, 2004 , and in revised form, August 4, 2004.

^* This work was supported by grants from the National Health and Medical Research Council (Australia) and the Australian Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 61-7-3346-2037; Fax: 61-7-3346-2101; E-mail: m.waters{at}imb.uq.edu.au.

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