Biological Activity of Ectodysplasin A Is Conditioned by Its Collagen and Heparan Sulfate Proteoglycan-binding Domains*
| Autor: | Laure Willen, Pascal Schneider, Aubry Tardivel, Manuel Favre, Lee Kim Swee, Stéphane Demotz, Marja L. Mikkola, Karine Ingold-Salamin, Olivier Gaide |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Keratinocytes
Biochemistry Collagen receptor Mice 0302 clinical medicine Ectodysplasins/*chemistry/deficiency/*metabolism Peptide sequence 0303 health sciences Cell Death NF-kappa B Biological activity Ectodysplasins Cross-Linking Reagents/pharmacology Cross-Linking Reagents 030220 oncology & carcinogenesis Protein Structure and Folding Collagen Keratinocytes/cytology/metabolism Genetic Engineering Hair/growth & development Tail Receptors Ectodysplasin Embryonic Development Biology Antibodies Cell Line 03 medical and health sciences Receptors Ectodysplasin/metabolism Animals Humans Amino Acid Sequence Protein Structure Quaternary Molecular Biology 030304 developmental biology Proteoglycan binding Cell Biology Molecular biology Heparan Sulfate Proteoglycans/*metabolism ddc:616.8 Protein Structure Tertiary Antibodies/pharmacology Collagen/metabolism Ectodysplasins/chemistry Ectodysplasins/deficiency Gene Expression Regulation Heparan Sulfate Proteoglycans/metabolism Keratinocytes/cytology Keratinocytes/metabolism NF-kappa B/metabolism Protein Multimerization Collagen type I alpha 1 Collagen/*metabolism Ectodysplasin A Heparan sulfate proteoglycan binding Heparan Sulfate Proteoglycans Hair |
| Zdroj: | J Biol Chem Journal of Biological Chemistry, Vol. 284, No 40 (2009) pp. 27567-27576 Journal of Biological Chemistry, vol. 284, no. 40, pp. 27567-27576 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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