Biological activity of ectodysplasin A is conditioned by its collagen and heparan sulfate proteoglycan-binding domains.
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.
Swee
Lee Kim
LK
Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
Ingold-Salamin
Karine
K
Tardivel
Aubry
A
Willen
Laure
L
Gaide
Olivier
O
Favre
Manuel
M
Demotz
Stéphane
S
Mikkola
Marja
M
Schneider
Pascal
P
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D003094:Collagen / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D053331:Ectodysplasins / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D047108:Embryonic Development; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D006197:Hair / Q000254:growth & development; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D053338:Receptors, Ectodysplasin / Q000378:metabolism; D013623:Tail
D000906:Antibodies; D003432:Cross-Linking Reagents; D053331:Ectodysplasins; D019812:Heparan Sulfate Proteoglycans; D016328:NF-kappa B; D053338:Receptors, Ectodysplasin; D003094:Collagen