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

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.

• Authors: Lee Kim Swee, Karine Ingold-Salamin, Aubry Tardivel, Laure Willen, Olivier Gaide, Manuel Favre, Stéphane Demotz, Marja Mikkola, Pascal Schneider
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 40 Pg. 27567-76 (Oct 02 2009) ISSN: 1083-351X [Electronic] United States
• PMID: 19657145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Cross-Linking Reagents
• Ectodysplasins
• Heparan Sulfate Proteoglycans
• NF-kappa B
• Receptors, Ectodysplasin
• Collagen

Topics

• 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