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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.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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