Identification of a motif associated with the lactogenic actions of human growth hormone.
Human growth hormone (hGH) stimulates somatogenic and lactogenic actions through the GH and prolactin (PRL) receptors, respectively. In contrast, non-primate GHs stimulate only somatotropic action. Phe44, of the human GH sequence is present in all hormones stimulating lactogenic action and absent in all hormones stimulating only somatotropic action. We speculate that the presence of Phe44 is a feature necessary for specifying lactogenic activity. In this report, the role of Phe44 was investigated by its deletion or substitution with alanine or leucine. Deletion of Phe44 or substitution with leucine did not significantly change the structure of hGH as determined by circular dichroism, absorbance, and fluorescence spectroscopies. In contrast, substitution of alanine perturbed the structure. Deletion of Phe44 reduced binding affinity for the lactogenic receptor, resulting in a reduced activation. Substitution with either alanine or leucine partially restored lactogenic receptor binding affinity, which correlated with the hormones' activity in the Nb2 rat lymphoma cells. All the recombinant hGHs had similar somatotropic activities in FDC-P1 cells transfected with the hGH receptor. These data indicate that the hydrophobic side chain of Phe44 is required for lactogenic receptor binding and activation but is unnecessary for somatotropic action.
Peterson
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Ohio State Biochemistry Program, Ohio State University, Columbus, Ohio 43210, USA.
Brooks
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D000409:Alanine / Q000737:chemistry; D000818:Animals; D001681:Biological Assay; D002942:Circular Dichroism; D003001:Cloning, Molecular; D013006:Growth Hormone / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007774:Lactation; D007930:Leucine / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry; D017433:Protein Structure, Secondary; D051381:Rats; D011981:Receptors, Prolactin / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000378:metabolism*; D011994:Recombinant Proteins; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D011981:Receptors, Prolactin; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D010649:Phenylalanine; D013006:Growth Hormone; D007930:Leucine; D000409:Alanine