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Zinc metalloproteinase-mediated cleavage of the human Nogo-66 receptor.

Walmsley, Adrian Robert, Mccombie, Gregor, Neumann, Ulf, Marcellin, David, Hillenbrand, Rainer, Mir, Anis Khusro and Frentzel, Stefan (2004) Zinc metalloproteinase-mediated cleavage of the human Nogo-66 receptor. Journal of Cell science, 117 (Pt 19). pp. 4591-4602. ISSN 0021-9533


The central nervous system myelin components oligodendrocyte-myelin glycoprotein, myelin-associated glycoprotein and the Nogo-66 domain of Nogo-A inhibit neurite outgrowth by binding the neuronal glycosyl-phosphatidylinositol-anchored Nogo-66 receptor (NgR) that transduces the inhibitory signal to the cell interior via a transmembrane co-receptor, p75NTR. Here, we demonstrate that human NgR expressed in human neuroblastoma cells is constitutively cleaved in a post-ER compartment to generate a lipid-raft associated C-terminal fragment that is present on the cell surface and a soluble N-terminal fragment that is released into the medium. Mass spectrometric analysis demonstrated that the N-terminal fragment terminated just after the C-terminus of the ligand-binding domain of NgR. In common with other shedding mechanisms, the release of this fragment was blocked by a hydroxamate-based inhibitor of zinc metalloproteinases, but not by inhibitors of other protease classes and up-regulated by treatment with the cellular cholesterol depleting agent methyl-beta-cyclodextrin. The N-terminal fragment bound Nogo-66 and blocked Nogo-66 binding to cell surface NgR but failed to associate with p75NTR, indicative of a role as a Nogo-66 antagonist. Furthermore, the N- and C-terminal fragments of NgR were detectable in human brain cortex and the N-terminal fragment was also present in human cerebrospinal fluid, demonstrating that NgR proteolysis occurs within the human nervous system. Our findings thus identify a potential cellular mechanism for the regulation of NgR function at the level of the receptor.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On author's personal web site; Publisher's version/PDF may be used
Keywords: Ectodomain shedding; Nogo-66 receptor; Zinc metalloproteinase
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Date Deposited: 14 Dec 2009 13:55
Last Modified: 31 Jan 2013 01:08


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