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J. Biol. Chem., Vol. 282, Issue 18, 13522-13531, May 4, 2007

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Role of the Spätzle Pro-domain in the Generation of an Active Toll Receptor Ligand^*

Alexander N. R. Weber, Supported by the Deutsches Krebsforschungszentrum, Heidelberg, Germany, and INSERM¹, Monique Gangloff, Martin C. Moncrieffe, Yann Hyvert^¶2, Jean-Luc Imler^¶, and Nicholas J. Gay³

From the Department of Biochemistry, Cambridge University, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom, ^¶UPR 9022-CNRS, Institut de Biologie Moléculaire et Cellulaire, 15 Rue René Descartes, 67084 Strasbourg Cedex, France, and German Cancer Research Centre (DKFZ), Angewandte Tumorvirologie, Im Neuenheimer Feld, 69242 Heidelberg, Germany

The cytokine Spätzle is the ligand for Drosophila Toll, the prototype of an important family of membrane receptors that function in embryonic patterning and innate immunity. A dimeric precursor of Spätzle is processed by an endoprotease to produce a form (C-106) that cross-links Toll receptor ectodomains and establishes signaling. Here we show that before processing the pro-domain of Spätzle is required for correct biosynthesis and secretion. We mapped two loss-of-function mutations of Spätzle to a discrete site in the pro-domain and showed that the phenotype arises because of a defect in biosynthesis rather than signaling. We also report that the pro-domain and C-106 remain associated after cleavage and that this processed complex signals with the same characteristics as the C-terminal fragment. These results suggest that before activation the determinants on C-106 that bind specifically to Toll are sequestered by the pro-domain and that proteolytic processing causes conformational rearrangements that expose these determinants and enables binding to Toll. Furthermore, we show that the pro-domain is released when the Toll extracellular domain binds to the complex, a finding that has implications for the generation of a signaling-competent Toll dimer.

Received for publication, January 3, 2007 , and in revised form, February 16, 2007.

^* This work was supported in part by the UK Medical Research Council, CNRS, and National Institutes of Health Grant PO1 AI44220. 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 Figs. S1–S3.

² Supported by a fellowship from the Ligue Nationale Contre le Cancer.

¹ To whom correspondence may be addressed. E-mail: alexander.weber{at}dkfz-heidelberg.de. ³ To whom correspondence may be addressed. Tel.: 44-1223-333626-334976; Fax: 44-1223-766002; E-mail: njg11{at}mole.bio.cam.ac.uk.

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