Mutations Leading to X-linked Hypohidrotic Ectodermal Dysplasia Affect Three Major Functional Domains in the Tumor Necrosis Factor Family Member Ectodysplasin-A

Autor: Sylvie Hertig, Aubry Tardivel, Summer L. Street, Laura Runkel, Pascal Schneider, Olivier Gaide, Jürg Tschopp, Jonathan Zonana, Betsy Ferguson, Konstantinos Alevizopoulos
Rok vydání: 2001
Předmět:
Glycosylation
X Chromosome
Genetic Linkage
Molecular Sequence Data
Enzyme-Linked Immunosorbent Assay
Biology
Ligands
Biochemistry
Cell Line
Structure-Activity Relationship
Recognition sequence
Ectodermal Dysplasia
Sequence Analysis
Protein
Alternative Splicing
Amino Acid Sequence
Chromatography
Gel
Dimerization
Dose-Response Relationship
Drug
Ectodermal Dysplasia/genetics
Ectodysplasins
Exons
Furin
Humans
Introns
Membrane Proteins/chemistry
Membrane Proteins/genetics
Mutation
Phenotype
Precipitin Tests
Protein Binding
Protein Structure
Tertiary
Recombinant Proteins/metabolism
Sequence Homology
Amino Acid
Subtilisins/metabolism
Tumor Necrosis Factor-alpha/chemistry
X Chromosome/genetics
medicine
splice
Subtilisins
Hypohidrotic ectodermal dysplasia
Molecular Biology
EDARADD
Tumor Necrosis Factor-alpha
Alternative splicing
Membrane Proteins
Cell Biology
medicine.disease
Molecular biology
Recombinant Proteins
biology.protein
Ectodysplasin A
Zdroj: Journal of Biological Chemistry, vol. 276, no. 22, pp. 18819-18827
ISSN: 0021-9258
DOI: 10.1074/jbc.m101280200
Popis: Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.
Databáze: OpenAIRE
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