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J. Biol. Chem., Vol. 280, Issue 15, 14563-14571, April 15, 2005

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Cleavage of p75 Neurotrophin Receptor by -Secretase and -Secretase Requires Specific Receptor Domains^*

Niccolò Zampieri, Chong-Feng Xu¶||, Thomas A. Neubert¶||, and Moses V. Chao**

From the Molecular Neurobiology Program, ^¶Structural Biology Program, Skirball Institute for Biomolecular Medicine and Departments of Cell Biology and ^||Pharmacology, New York University School of Medicine, New York, New York 10016

The p75 neurotrophin receptor (p75^NTR), a member of the tumor necrosis factor superfamily of receptors, undergoes multiple proteolytic cleavage events. These events are initiated by an -secretase-mediated release of the extracellular domain followed by a -secretase-mediated intramembrane cleavage. However, the specific determinants of p75^NTR cleavage events are unknown. Many other substrates of -secretase cleavage have been identified, including Notch, amyloid precursor protein, and ErbB4, indicating there is broad substrate recognition by -secretase. Using a series of deletion mutations and chimeric receptors of p75^NTR and the related Fas receptor, we have identified domains that are essential for p75^NTR proteolysis. The initial -secretase cleavage was extracellular to the transmembrane domain. Unfortunately, deletion mutants were not capable of defining the requirements of ectodomain shedding. Although this cleavage is promiscuous with respect to amino acid sequence, its position with respect to the transmembrane domain is invariant. The generation of chimeric receptors exchanging different domains of noncleavable Fas receptor with p75^NTR, however, revealed that a discrete domain above the membrane is sufficient for efficient cleavage of p75^NTR. Mass spectrometric analysis confirmed the cleavage can occur with a truncated p75^NTR displaying only 15 extracellular amino acids in the stalk region.

Received for publication, November 16, 2004 , and in revised form, January 18, 2005.

^* This work was supported by National Institutes of Health Grants NS21072, CA56490, and HD23315 (to M. V. C.) and National Institutes of Health Shared Instrumentation Grant S10 RR01-7990 (to T. A. N.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

^** To whom correspondence should be addressed: Skirball Inst. for Biomolecular Medicine, New York University School of Medicine, 540 First Ave., New York, NY 10016. Tel.: 212-263-0761; Fax: 212-263-0723; E-mail: chao{at}saturn.med.nyu.edu.

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