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Alteration in the Receptor Binding Specificity of Human Growth Hormone by Genomic Exon Exchange

Department of Human Genetics, University of Pennsylvania Philadelphia, Pennsylvania 19104–6145
Department of Medicine, University of Pennsylvania Philadelphia, Pennsylvania 19104–6145
Department of the Howard Hughes Medical Institute, University of Pennsylvania Philadelphia, Pennsylvania 19104–6145
Laboratory of Molecular Endocrinology, Royal Victoria Hospital, McGill University Montreal, Quebec H3A1A1, Canada

Address requests for reprints to: Dr. Nancy E. Cooke, University of Pennsylvania, Room 700, Clinical Research Building, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104–6145.

Abstract

The biological activities of the GH-PRL family of hormones are mediated by selective binding to two classes of cell membrane receptors, somatogen and lactogen. Primate GH such as human GH (hGH) are unusual in that they bind to both classes of receptors. Replacement of exons 3 or 4 of the hGH gene by the corresponding exons of the rat PRL or rat GH genes results in the synthesis of chimeric proteins which retain the ability to bind to lactogen receptors but can no longer bind to somatogen receptors. This selective loss of somatogen receptor binding in the chimeric proteins suggests that certain of the structural determinants of somatogen and lactogen receptor binding activities in hGH are distinct and can be separately modified by a limited number of amino acid substitutions.

FOOTNOTES

This investigation was supported in part by NIH Grant P50GM-32592 (to N.E.C. and S.A.L.), Basic Research Grant 1–1015 from the National Foundation, March of Dimes (NEC), and grants from both the Medical Research Council and the National Cancer Institutes of Canada (to P.A.K.).

Received for publication August 21, 1989. Revision received September 28, 1989. Accepted for publication October 3, 1989.