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Originally published In Press as doi:10.1074/jbc.M001236200 on March 16, 2000

J. Biol. Chem., Vol. 275, Issue 21, 15652-15656, May 26, 2000
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The Binding between the Stem Regions of Human Growth Hormone (GH) Receptor Compensates for the Weaker Site 1 Binding of 20-kDa Human GH (hGH) than That of 22-kDa hGH*

Bunkichi TsunekawaDagger , Mitsufumi WadaDagger §, Miwa IkedaDagger , Shinichi Banba, Hironori Kamachi, Eishi Tanaka, and Masaru HonjoDagger

From the Dagger  Pharmaceuticals Section, Life Sciences Laboratory and the  Computer Science Department, Material Science Laboratory, Mitsui Chemicals, Inc., 1144 Togo, Mobara-shi, Chiba 297-0017, Japan

Despite the lower site 1 affinity of the 20-kDa human growh hormone (20K-hGH) for the hGH receptor (hGHR), 20K-hGH has the same hGHR-mediated activity as 22-kDa human GH (22K-hGH) at low hGH concentration and even higher activity at high hGH concentration. This study was performed to elucidate the reason why 20K-hGH can activate hGHR to the same level as 22K-hGH. To answer the question, we hypothesized that the binding between the stem regions of hGHR could compensate for the weaker site 1 binding of 20K-hGH than that of 22K-hGH in the sequential binding with hGHR. To demonstrate it, we prepared 15 types of alanine-substituted hGHR gene at the stem region and stably transfected them into Ba/F3 cells. Using these cells, we measured and compared the cell proliferation activities between 20K- and 22K-hGH. As a result, the activity of 20K-hGH was markedly reduced than that of 22K-hGH in three types of mutant hGHR (T147A, H150A, and Y200A). Regarding these mutants, the dissociation constant of hGH at the first and second step (KD1 and KD2) in the sequential binding with two hGHRs was predicted based on the mathematical cell proliferation model and computational simulation. Consequently, it was revealed that the reduction of the activity in 20K-hGH was attributed to the change of not KD1 but KD2. In conclusion, these findings support our hypothesis, which can account for the same potencies for activating hGHR between 20K- and 22K-hGH, although the site 1 affinity of 20K-hGH is lower than that of 22K-hGH.


* The costs of publication of this article were defrayed in part by the payment of page charges. The 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.: 81 475 25 6728; Fax: 81 475 25 6553; E-mail: mitsufumi.wada@mitsui-chem.co.jp.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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