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J. Biol. Chem., Vol. 279, Issue 25, 26013-26018, June 18, 2004

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Enhancement of the Antagonistic Potency of Transforming Growth Factor- Receptor Extracellular Domains by Coiled Coil-induced Homo- and Heterodimerization^*

Gregory De Crescenzo, Phuong L. Pham, Yves Durocher, Heman Chao¶, and Maureen D. O'Connor-McCourt||

From the Cell Signaling and Proteomic Group, Health Sector, and Bioprocess Platform, Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, and ^¶Helix BioPharma Corporation, Aurora, Ontario L4G 6X7, Canada

Transforming growth factor- (TGF-) plays a causal role in several human pathologies including fibrotic diseases and metastasis. TGF- signaling is mediated through its interaction with three types of cell surface receptors, RI, RII, and RIII. The soluble ectodomains of RII and RIII bind to TGF-, making them attractive candidates to sequester TGF- and inhibit its activity. To optimize the activity of the ectodomains, we studied the effect of artificially dimerizing them upon their kinetics of binding to TGF- using an optical biosensor and studied their antagonistic potencies using an in vitro signaling assay. We fused the RII ectodomain and the membrane-proximal ligand-binding domain of the RIII ectodomain to de novo designed heterodimerizing coil strands and demonstrated that the coil strands within the fusion proteins were capable of promoting the dimerization of the coil-tagged ectodomains. Our results indicate that coiled coil-induced dimerization of the ectodomains stabilized their interaction with TGF- as compared with the monomeric ectodomains. Also, in contrast to the monomeric ectodomains, which did not block signaling, the coiled coil-induced dimers were characterized by antagonistic potencies in the low nanomolar range.

Received for publication, January 20, 2004 , and in revised form, March 16, 2004.

^* 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.

^|| To whom correspondence should be addressed: Cell Signaling and Proteomic Group, Health Sector, Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Ave., Montreal, Quebec H4P 2R2, Canada. Tel.: 514-496-6382; Fax: 514-496-5143; E-mail: maureen.o'connor{at}nrc.ca.

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