ABSTRACT

The proteolytic cleavage of a G protein-coupled peptide hormone receptor, the renal V vasopressin receptor, by a plasma membrane proteinase was investigated. In the absence of protease inhibitors during incubation of bovine kidney membranes with a photoreactive vasopressin agonist, V receptor truncation leads to a labeled receptor fragment with M 30,000. The V receptor-degrading enzyme could be completely inhibited by zinc ions yielding the native V receptor glycoprotein with M 58,000. Studies with inhibitors of metalloendopeptidases involved in peptide hormone metabolism and with peptide substrates spanning the V receptor cleavage site classify the receptor protease as metalloendoproteinase with specificity for longer substrates. Comparison of the NH-terminal protein sequence of the truncated M 30,000 V receptor with the sequence deduced from the cDNA of the cloned bovine V receptor shows that cleavage occurs between Gln and Val of the second transmembrane helix close to an extracellular agonist binding site. V receptor proteolysis was dependent on the presence of a hormonal ligand. It occurred rapidly after hormone binding and led to a loss of ligand binding properties of the truncated V receptor. The data suggest that the endogenous V receptor-degrading metalloendoproteinase regulates V receptor function. The novel pathway may contribute to the termination of signal transmission.

FOOTNOTES

*

This work was supported by Grant SFB 169 from the Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed: Max-PlanckInstitute of Biophysics, Kennedyallee 70, 60596 Frankfurt am Main, Germany. Tel.: 69-6303-267; Fax: 69-6303-244.

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The abbreviations used are: HPLC, high performance liquid chromatography; AEBSF, 4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride; AVP, [8-arginine] vasopressin; DDAVP, 1- deamino [8-D-arginine] vasopressin; FAB, fast atom bombardment; PAGE, polyacrylamide gel electrophoresis; Hepps, 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid.

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Ufer, E., Postina, R., Gorbulev, V., and Fahrenholz, F.(1995) FEBS Lett, in press.

()

E. Kojro, E. Ufer, and F. Fahrenholz, unpublished observation.

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