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First published online 27 July 2004
doi: 10.1242/jcs.01263

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Release of a membrane-bound death domain by -secretase processing of the p75^NTR homolog NRADD

¹ Department of Pathology, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
² Howard Hughes Medical Institute, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA

^* Author for correspondence (e-mail: vincenz{at}umich.edu)

Accepted 7 April 2004

Neurotrophin receptor alike death domain protein (NRADD) is a death-receptor-like protein with a unique ectodomain and an intracellular domain homologous to p75^NTR. Expression of NRADD results in apoptosis, but only in certain cell types. This paper characterizes the expression and proteolytic processing of the mature 55 kDa glycoprotein. N-terminally truncated NRADD is processed by a -secretase activity that requires presenilins and has the same susceptibility to -secretase inhibitors as the secretion of amyloid ß (Aß). The ectodomain of endogenous NRADD is shed by activation of metalloproteinases. Inhibitor studies provide evidence that NRADD is cleaved in two steps typical of regulated intramembrane proteolysis (RIP). Inhibition of -secretase abrogates both the production of the soluble intracellular domain of NRADD and the appearance of NRADD in subnuclear structures. Thus, solubilized death domains with close homology to p75^NTR might have a nuclear function. Furthermore, presenilin deficiency leads to abnormally glycosylated NRADD and overexpression of presenilin 2 inhibits NRADD maturation, which is dependent on the putative active site residue D366 but not on -secretase activity. Our results demonstrate that NRADD is an additional -secretase substrate and suggest that drugs against Alzheimer's disease will need to target -secretase in a substrate-specific manner.

Key words: -Secretase, Death domain, Metalloproteinases, NRADD, Presenilin

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