Scientific article

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

Published inThe Journal of biological chemistry, vol. 284, no. 40, p. 27567-27576
Publication date2009

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.

  • 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
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: The Journal of biological chemistry, 2009, vol. 284, n° 40, p. 27567–27576. doi: 10.1074/jbc.M109.042259
Updates (1)
ISSN of the journal0021-9258

Technical informations

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