1. Biological Activity of Ectodysplasin A Is Conditioned by Its Collagen and Heparan Sulfate Proteoglycan-binding Domains.
- Author
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Lee Kim Swee, lngold-Salamin, Karine, Tardivel, Aubry, WiIIen, Laure, Gaide, Olivier, Favre, Manuel, Demotz, Stéphane, Mikkola, Marja, and Schneider, Pascal
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ECTODERMAL dysplasia , *PROTEOGLYCANS , *TRANSCRIPTION factors , *IMMUNOGLOBULINS , *KERATINOCYTES , *TUMOR necrosis factors - Abstract
Mutations in the TNF family ligand EDA1 cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition characterized by defective development of skin appendages. The EDA1 protein displays a proteolytic processing site responsible for its conversion to a soluble form, a collagen domain, and a trimeric TNF homology domain (THD) that binds the receptor EDAR. In-frame deletions in the collagen domain reduced the thermal stability of EDA1, Removal of the collagen domain decreased its activity about 100-fold, as measured with natural and engineered EDA1-responsive cell lines. The collagen domain could be functionally replaced by multimerization domains or by cross-linking antibodies, suggesting that it functions as an oligomerization unit. Surprisingly, mature soluble EDA1 containing the collagen domain was poorly active when administered in newborn, EDA-deficient (Tabby) mice. This was due to a short stretch of basic amino acids located at the N terminus of the collagen domain that confers EDA1 with proteoglycan binding ability. In contrast to wild-type EDA1, EDA1 with mutations in this basic sequence was a potent inducer of tail hair development in vivo, Thus, the collagen domain activates EDA1 by multimerization, whereas the proteoglycanbinding domain may restrict the distribution of endogeneous EDA1 in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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