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A ß-Turn Endocytic Code Is Required for Optimal Internalization of the Growth Hormone Receptor but Not for -Adaptin Association

INSERM U344 (L.V., A.P., M.E.) Faculté de Médecine Necker F-75730 Paris, Cedex 15, France
Leuven Poultry Research Group Zoological Institute (L.V., E.R.K.) and Department of Animal Sciences (E.D.) Katholieke Universiteit Leuven B-3000 Leuven, Belgium

Intracellular trafficking of GH and its receptor, more particularly the chicken GH receptor (cGHR), was examined in COS-7 cells using biochemical and structural studies. Internalization of radioactive GH by the cGHR is reduced as compared with the rat GHR. On the contrary, activation of gene transcription through Janus kinase-2 was similar for both species. Secondary structures of the cytoplasmic domain of chicken and rat GHR were compared, since ß-turns were reported as internalization signals. The substitution of Pro³³⁵-Asp³³⁶, present in mammalian GH receptors, with Thr³⁰⁷-Gln³⁰⁸ in the cGHR leads to the loss of a ß-turn within a conserved cytoplasmic region. Mutational analysis indicated that the lower rate of internalization of cGHR, as compared with mammalian GHR, was due to this motif. Our data further show that -adaptin, a subunit of adaptor protein AP-2, associates with the GHR upon hormone stimulation. The clathrin-coated pit pathway therefore seems to be involved in the endocytosis of cGHR, as AP-2 is known to intervene in the recruitment of receptors to these pits. Interaction with -adaptin may occur through a common epitope of the chicken and mammalian GHR, since receptors from both species bind similar amounts of -adaptin; alternatively, two different epitopes with similar affinity may be involved. Therefore, not -adaptin but an uncharacterized factor, presumably interacting with the identified ß-turn endocytic code, is responsible for the difference in internalization kinetics. Finally, the present study illustrates that functional amino acid motifs of receptors can be derived from comparative studies.

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