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J. Biol. Chem., Vol. 279, Issue 30, 31823-31832, July 23, 2004

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Autocatalytic Cleavage of the EMR2 Receptor Occurs at a Conserved G Protein-coupled Receptor Proteolytic Site Motif^*

Hsi-Hsien Lin, Gin-Wen Chang, John Q. Davies¶, Martin Stacey, James Harris, and Siamon Gordon||

From the Sir William Dunn School of Pathology, The University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom

Post-translational cleavage at the G protein-coupled receptor proteolytic site (GPS) has been demonstrated in many class B2 G protein-coupled receptors as well as other cell surface proteins such as polycystin-1. However, the mechanism of the GPS proteolysis has never been elucidated. Here we have characterized the cleavage of the human EMR2 receptor and identified the molecular mechanism of the proteolytic process at the GPS. Proteolysis at the highly conserved His-LeuSer⁵¹⁸ cleavage site can occur inside the endoplasmic reticulum compartment, resulting in two protein subunits that associate noncovalently as a heterodimer. Site-directed mutagenesis of the P⁺¹ cleavage site (Ser⁵¹⁸) shows an absolute requirement of a Ser, Thr, or Cys residue for efficient proteolysis. Substitution of the P^-2 His residue to other amino acids produces slow processing precursor proteins, which spontaneously hydrolyze in a defined cell-free system. Further biochemical characterization indicates that the GPS proteolysis is mediated by an autocatalytic intramolecular reaction similar to that employed by the N-terminal nucleophile hydrolases, which are known to activate themselves by self-catalyzed cis-proteolysis. We propose here that the autoproteolytic cleavage of EMR2 represents a paradigm for the other GPS motif-containing proteins and suggest that these GPS proteins belong to a cell surface receptor subfamily of N-terminal nucleophile hydrolases.

Received for publication, March 17, 2004 , and in revised form, May 13, 2004.

^* This study was supported by British Heart Foundation Grant PG/02/144 (to H.-H. L.) and the Wellcome Trust (to G.-W. C. and M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶ Recipient of an Oxford Nuffield Medical Fellowship.

^|| Supported by grants from the Medical Research Council, United Kingdom.

To whom correspondence should be addressed. Tel.: 44-1865-275532; Fax: 44-1865-275515; E-mail: hsi-hsien.lin{at}path.ox.ac.uk.

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