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Biological activity of ectodysplasin A is conditioned by its collagen and heparan sulfate proteoglycan-binding domains

Swee, Lee Kim
Ingold-Salamin, Karine
Tardivel, Aubry
Willen, Laure
Favre, Manuel
Demotz, Stéphane
Mikkola, Marja
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Published in The Journal of biological chemistry. 2009, vol. 284, no. 40, p. 27567-27576
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 proteoglycan-binding domain may restrict the distribution of endogeneous EDA1 in vivo.
Keywords Amino Acid SequenceAnimalsAntibodies/pharmacologyCell DeathCell LineCollagen/*metabolismCross-Linking Reagents/pharmacologyEctodysplasins/*chemistry/deficiency/*metabolismEmbryonic DevelopmentGene Expression RegulationGenetic EngineeringHair/growth & developmentHeparan Sulfate Proteoglycans/*metabolismHumansKeratinocytes/cytology/metabolismMiceNF-kappa B/metabolismProtein MultimerizationProtein Structure, QuaternaryProtein Structure, TertiaryReceptors, Ectodysplasin/metabolismTail
PMID: 19657145
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Other version: http://www.jbc.org/content/284/40/27567.full.pdf
Research group Voies d'activation de l'immunité innée au niveau de la peau (156)
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SWEE, Lee Kim et al. Biological activity of ectodysplasin A is conditioned by its collagen and heparan sulfate proteoglycan-binding domains. In: The Journal of biological chemistry, 2009, vol. 284, n° 40, p. 27567-27576. doi: 10.1074/jbc.M109.042259 https://archive-ouverte.unige.ch/unige:20121

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Deposited on : 2012-04-23

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