Identification of a cytoplasmic Ser-Thr-Leu motif that determines agonist-induced internalization of the AT1 angiotensin receptor

L. Hunyady, Márta Bor, Tamas Balla, Kevin J. Catt

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Abstract

The type 1 angiotensin II (AT1) receptor undergoes rapid endocytosis and down-regulation after agonist binding. In studies on the structural determinants of agonist-induced endocytosis, serial deletions in the cytoplasmic tail of the rat AT1a receptor showed that the carboxyl-terminal 22 amino acids are not necessary for its internalization. However, internalization was markedly impaired by the removal of one additional amino acid (Leu337) and was reduced by 95% after removal of Ser335 and Thr?336. Single alanine replacements of amino acids in this region showed that individual substitutions of Thr332, Ser335, Thr336, Leu337, and Ser338 caused moderate but significant impairment of the internalization rate. Replacement of both Ser335 and Thr336 with alanine residues further impaired the internalization rate, and triple alanine replacement of the Ser-Thr-Leu motif reduced internalization to almost the same extent as the corresponding tail deletion mutant. The Ser-Thr-Leu motif is highly conserved in mammalian AT1 receptors but is not present in the noninternalizing type 2 angiotensin II receptor. These data demonstrate that a serine/ threonine-rich region including Leu337 in the cytoplasmic tail of the AT1 receptor is a major requirement for endocytosis of the hormone-receptor complex and support the concept that similar motifs in other G protein-coupled receptors are determinants of their agonist-induced internalization.

Original languageEnglish
Pages (from-to)31378-31382
Number of pages5
JournalJournal of Biological Chemistry
Volume269
Issue number50
Publication statusPublished - Dec 16 1994

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Angiotensin Type 1 Receptor
Endocytosis
Alanine
Tail
Amino Acids
Angiotensin Type 2 Receptor
Angiotensin Receptors
Threonine
G-Protein-Coupled Receptors
Angiotensin II
Serine
Rats
Substitution reactions
Down-Regulation
Hormones

ASJC Scopus subject areas

  • Biochemistry

Cite this

Identification of a cytoplasmic Ser-Thr-Leu motif that determines agonist-induced internalization of the AT1 angiotensin receptor. / Hunyady, L.; Bor, Márta; Balla, Tamas; Catt, Kevin J.

In: Journal of Biological Chemistry, Vol. 269, No. 50, 16.12.1994, p. 31378-31382.

Research output: Contribution to journalArticle

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