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Human growth hormone site 2 lactogenic activity requires a distant tyrosine164
Author(s) -
Duda Karen M.,
Brooks Charles L.
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)00416-0
Subject(s) - prolactin , prolactin receptor , binding site , receptor , agonist , thyrotropin releasing hormone receptor , endocrinology , hormone , medicine , chemistry , biology , hormone receptor , biochemistry , genetics , cancer , breast cancer
Comparison of crystallographic structures of human growth hormone, either bound to the prolactin receptor or free of receptors, reveals that human growth hormone binding to the prolactin receptor at site 1 is associated with a structural change in human growth hormone that influences the organization of residues which constitute site 2. We have identified Tyr 164 as a residue that is critical for the propagation of this structural rearrangement. Tyr 164 is a structural epitope for site 1 and is distal to site 2. Mutation of Tyr 164 to glutamic acid (Y164E) does not affect the somatotrophic activity, absorption or fluorescence spectra or binding to the human prolactin receptor when compared to wild‐type human growth hormone, indicating the subtle effects of the mutation. Lactogenic assays using extended concentrations of Y164E human growth hormone produce dose‐response curves that are characterized by a right‐shifted agonist phase and an unchanged antagonist phase when compared to wild‐type human growth hormone. These results indicate that Tyr 164 is required for the lactogenic activity of human growth hormone and that mutation to glutamic acid disrupts the lactogenic function of site 2.