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J Biol Chem, Vol. 273, Issue 29, 18316-18324, July 17, 1998

Mutation of Individual Serine Residues in the C-terminal Tail of the Lutropin/Choriogonadotropin Receptor Reveal Distinct Structural Requirements for Agonist-induced Uncoupling and Agonist-induced Internalization

Maria de Fatima M. Lazari, Jennifer E. Bertrand, Kazuto Nakamura, Xuebo Liu, Jason G. Krupnick^**, Jeffrey L. Benovic^**, and Mario Ascoli

From the  Department of Pharmacology, The University of Iowa College of Medicine, Iowa City, Iowa 52242 and the ^** Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

We have previously mapped the agonist-induced phosphorylation of the rat lutropin/choriogonadotropin receptor (rLHR) to a locus of four serines (Ser⁶³⁵, Ser⁶³⁹, Ser⁶⁴⁹, and Ser⁶⁵²) located in the C-terminal tail. The removal or mutation of this locus delays the time course of agonist-induced uncoupling of the rLHR from its effector system without affecting the overall magnitude of uncoupling, and it retards the endocytosis of the agonist-receptor complex.

We have now prepared and analyzed four new rLHR mutants in which each of these serines were individually mutated to alanines. The data presented show that each mutation reduces agonist-promoted rLHR phosphorylation by 20-40%. Mutation of Ser⁶³⁵ or Ser⁶³⁹ delayed the time course of agonist-induced uncoupling to about the same extent as the simultaneous mutation of all four serines. Mutation of Ser⁶³⁵ or Ser⁶³⁹ also retarded agonist-induced internalization, but the magnitude of this decrease was less than that induced by the simultaneous mutation of all four serines. Mutation of Ser⁶⁴⁹ had no effect on agonist-induced uncoupling but retarded agonist-induced internalization to the same extent as the simultaneous mutation of all four serines. Mutation of Ser⁶⁵² has little or no effect on either of these two parameters.

Co-transfection studies with dominant-negative arrestins and dominant-negative dynamin reveal that, despite differences in their rates of internalization, rLHR-wild-type, rLHR-S639A, and rLHR-S649A are internalized by an arrestin- and dynamin-dependent pathway.

These data show that the structural requirements needed for the agonist-induced uncoupling and internalization of the rLHR are distinct.

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