The Crystal Structures of EDA-A1 and EDA-A2: Splice Variants with Distinct Receptor Specificity

EDA is a tumor necrosis factor family member involved in ectodermal development. Splice variants EDA-A1 and EDA-A2 differ only by the presence of Glu 308 and Val 309 in the expected receptor binding region of EDA-A1 but not EDA-A2. This two amino acid difference functions as a switch controlling rec...

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Bibliographic Details
Published in:Structure (London) 2003-12, Vol.11 (12), p.1513-1520
Main Authors: Hymowitz, Sarah G, Compaan, Deanne M, Yan, Minhong, Wallweber, Heidi J.A, Dixit, Vishva M, Starovasnik, Melissa A, de Vos, Abraham M
Format: Article
Language:English
Subjects:
Alternative Splicing
Binding Sites
Crystallography, X-Ray
Ectodysplasins
Escherichia coli - metabolism
Humans
Ligands
Membrane Proteins - chemistry
Membrane Proteins - genetics
Models, Biological
Models, Molecular
Mutation
Protein Binding
Protein Conformation
Protein Isoforms
Protein Structure, Secondary
Protein Structure, Tertiary
Static Electricity
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Summary:EDA is a tumor necrosis factor family member involved in ectodermal development. Splice variants EDA-A1 and EDA-A2 differ only by the presence of Glu 308 and Val 309 in the expected receptor binding region of EDA-A1 but not EDA-A2. This two amino acid difference functions as a switch controlling receptor specificity. EDA-A1 binds only to EDAR, while EDA-A2 is specific for XEDAR. In order to understand the structural basis of this switch, we determined the X-ray crystal structures of the TNF domain of both EDA-A1 and EDA-A2 at 2.3 Å and 2.2 Å, respectively. While the backbone conformation around the splice difference is similar in both isoforms, the conformation of the following loop, the surface charge, and the shape of the expected receptor binding site differ significantly.
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2003.11.009