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; Gaide, Olivier; Favre, Manuel; Demotz, Stéphane; Mikkola, Marja; Schneider, Pascal

doi:10.1074/jbc.M109.042259

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Title		Biological activity of ectodysplasin A is conditioned by its collagen and heparan sulfate proteoglycan-binding domains
Authors		Swee, Lee Kim Ingold-Salamin, Karine Tardivel, Aubry Willen, Laure Gaide, Olivier Favre, Manuel Demotz, Stéphane Mikkola, Marja Schneider, Pascal show all authors [1 - 9]
Published in		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 Sequence — Animals — Antibodies/pharmacology — Cell Death — Cell Line — Collagen/metabolism — Cross-Linking Reagents/pharmacology — Ectodysplasins/chemistry/deficiency/metabolism — Embryonic Development — Gene Expression Regulation — Genetic Engineering — Hair/growth & development — Heparan Sulfate Proteoglycans/metabolism — Humans — Keratinocytes/cytology/metabolism — Mice — NF-kappa B/metabolism — Protein Multimerization — Protein Structure, Quaternary — Protein Structure, Tertiary — Receptors, Ectodysplasin/metabolism — Tail
Identifiers		DOI: 10.1074/jbc.M109.042259 PMID: 19657145
Full text		Article - Limited access to UNIGE Other version: http://www.jbc.org/content/284/40/27567.full.pdf
Structures		Faculté de médecine / Section de médecine clinique / Département des neurosciences cliniques
Research group		Voies d'activation de l'immunité innée au niveau de la peau (156)
Citation (ISO format)		SWEE, Lee Kim et al. Biological activity of ectodysplasin A is conditioned by its collagen and heparan sulfate proteoglycan-binding domains. In: Journal of Biological Chemistry, 2009, vol. 284, n° 40, p. 27567-27576. https://archive-ouverte.unige.ch/unige:20121