Aspartate 171 is the major primate-specific determinant of human growth hormone

Engineering porcine growth hormone to activate the human receptor

Stuart N. Behncken*, Scott W. Rowlinson, Jennifer E. Rowland, Becky L. Conway-Campbell, Thea A. Monks, Michael J. Waters

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

It has been known for more than 4 decades that only primate growth hormones are effective in primate species, but it is only with the availability of the 2.8 Å structure of the human growth hormone (hGH)·hGH- binding protein (hGHBP)2 complex that Souza and co-workers (Souza, S. C., Frick, G. P., Wang, X., Kopchick, J. J., Lobo, R. B., and Goodman, H. M. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 959-963) were able to provide evidence that Arg-43 on the primate receptor is responsible. Here we have examined systematically the interaction between Arg-43 (primate receptor) or Leu-43 (non-primate receptors) and their complementary hormone residues Asp- 171 (primate GH) and His-170 (non-primate hormones) in a four-way comparison involving exchanges of histidine and aspartate and exchanges of arginine and leucine. BAF/B03 lines were created and characterized which stably expressed hGH receptor, R43L hGH receptor, rabbit GH receptor, and IA3R rabbit GH receptor. These were examined for site 1 affinity, for the ability to bind intact cells, and for proliferative biopotency using hGH, D171H hGH, porcine GH, or H170D porcine GH. We find that the single interaction between Arg-43 and His-170/171 is sufficient to explain virtually all of the primate species specificity, and this is congruent with the crystal structure. Accordingly, for the first time we have been able to engineer a nonprimate hormone to bind to and activate the human GH receptor.

Original languageEnglish
Pages (from-to)27077-27083
Number of pages7
JournalJournal of Biological Chemistry
Volume272
Issue number43
DOIs
Publication statusPublished - 1997
Externally publishedYes

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