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Download Hi-Res ImageDownload to MS-PowerPointCite This:Biochemistry 2009, 48, 14, 3230-3238
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Dissociation of the Subunits of the Calcium-Independent Receptor of α-Latrotoxin as a Result of Two-Step Proteolysis†

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Department of Pharmacology, New York University School of Medicine, New York, New York 10016, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia 117997, and Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016
†Supported by Public Health Service Grants R01NS35098 from the NINDS and R03 TW007210 from the FIC, Molecular and Cellular Biology Program and Basic Sciences to Medicine Program of the Russian Academy of Sciences, and RFBR Grant 06-04-49706-a (to A.G.P.) and by NIH Shared Instrumentation Grant 1 S10 RR14662-01 (to T.A.N.).
* To whom correspondence should be addressed: e-mail, [email protected]; phone, +7(495)335-4177; fax, +7(495)335-7103.
‡Department of Pharmacology, New York University School of Medicine.
§Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry.
∥Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine.
Cite this: Biochemistry 2009, 48, 14, 3230–3238
Publication Date (Web):January 22, 2009
https://doi.org/10.1021/bi802163p
Copyright © 2009 American Chemical Society
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    Abstract

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    CIRL (the calcium-independent receptor of α-latrotoxin), a neuronal cell surface receptor implicated in the regulation of exocytosis, is a member of the GPS family of chimeric cell adhesion/G protein-coupled receptors. The predominant form of CIRL is a membrane-bound complex of two subunits, p120 and p85. Extracellularly oriented p120 contains hydrophilic cell adhesion domains, whereas p85 is a heptahelical membrane protein. Both subunits are encoded by the same gene and represent products of intracellular proteolytic processing of the CIRL precursor. In this study, we demonstrate that a soluble form of CIRL also exists in vitro and in vivo. It results from the further cleavage of CIRL by a second protease. The site of the second cleavage is located in the short N-terminal extracellular tail of p85, between the GPS domain and the first transmembrane segment of CIRL. Thus, the soluble form of CIRL represents a complex of p120 noncovalently bound to a 15 amino acid residue N-terminal peptide fragment of p85. We have previously shown that mutations of CIRL in the GPS domain inhibit intracellular proteolytic processing and also result in the absence of the receptors from the cell surface. Our current data suggest that although CIRL trafficking to the cell membrane is impaired by mutations in the GPS region, it is not blocked completely. However, at the cell surface, the noncleaved mutants are preferentially targeted by the second protease that sheds the extracellular subunit. Therefore, the two-step proteolytic processing may represent a regulatory mechanism that controls cell surface expression of membrane-bound and soluble forms of CIRL.

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