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J. Biol. Chem., Vol. 280, Issue 39, 33453-33460, September 30, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/39/33453    most recent M503189200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Aurikko, J. P. Articles by Blundell, T. L. Search for Related Content PubMed PubMed Citation Articles by Aurikko, J. P. Articles by Blundell, T. L. Social Bookmarking                      What's this?

Characterization of Symmetric Complexes of Nerve Growth Factor and the Ectodomain of the Pan-neurotrophin Receptor, p75^NTR*

Jukka P. Aurikko1, Brandon T. Ruotolo, J. Günter Grossmann¶, Martin C. Moncrieffe, Elaine Stephens, Veli-Matti Leppänen||, Carol V. Robinson, Mart Saarma||, Ralph A. Bradshaw****, and Tom L. Blundell

From the Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom, the Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom, the ^¶Synchrotron Radiation Department, CCLRC Daresbury Laboratory, Warrington WA4 AD, United Kingdom, the ^**Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland, and the ^**Department of Physiology & Biophysics, University of California, Irvine, California 92697

Nerve growth factor (NGF) is the ligand for two unrelated cellular receptors, TrkA and p75^NTR, and acts as a mediator in the development and maintenance of the mammalian nervous system. Signaling through TrkA kinase domains promotes neuronal survival, whereas activation of the p75^NTR "death domains" induces apoptosis under correct physiological conditions. However, co-expression of these receptors leads to enhanced neuronal survival upon NGF stimulation, possibly through a ternary p75^NTR·NGF·TrkA complex. We have expressed human p75^NTR ligand binding domain as a secreted glycosylated protein in Trichoplusia ni cells. Following assembly and purification of soluble p75^NTR·NGF complexes, mass spectrometry, analytical ultracentrifugation, and solution x-ray scattering measurements are indicative of 2:2 stoichiometry, which implies a symmetric complex. Molecular models of the 2:2 p75^NTR·NGF complex based on these data are not consistent with the further assembly of either symmetric (2:2:2) or asymmetric (2:2:1) ternary p75^NTR·NGF·TrkA complexes.

Received for publication, March 23, 2005 , and in revised form, July 8, 2005.

^* This work was supported in part by Wellcome Trust grants, a Cambridge University Parke-Davis Visiting Fellow Award, and by the Walters-Kundert trust and Biotechnology and Biological Sciences Research Council (to B. T. R., C. V. R., and E. 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.

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

¹ To whom correspondence should be addressed: Dept. of Biochemistry, University of Cambridge, 80 Tennis Ct. Rd., Cambridge CB2 1GA, UK. Tel.: 44-0-1223-766028; Fax: 44-0-1223-766002; E-mail: jukka{at}cryst.bioc.cam.ac.uk.

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