Crystal Structure of SEDL and Its Implications for a Genetic Disease Spondyloepiphyseal Dysplasia Tarda

SEDL is an evolutionarily highly conserved protein in eukaryotic organisms. Deletions or point mutations in theSEDL gene are responsible for the genetic disease spondyloepiphyseal dysplasia tarda (SEDT), an X-linked skeletal disorder. SEDL has been identified as a component of the transport protein...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-12, Vol.277 (51), p.49863-49869
Main Authors: Jang, Se Bok, Kim, Yeon-Gil, Cho, Yong-Soon, Suh, Pann-Ghill, Kim, Kyung-Hwa, Oh, Byung-Ha
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Carrier Proteins - chemistry
Crystallography, X-Ray
Escherichia coli - metabolism
Gene Deletion
Genetic Linkage
Golgi Apparatus - metabolism
Humans
Membrane Proteins - chemistry
Membrane Transport Proteins
Mice
Models, Molecular
Molecular Sequence Data
Mutation
Mutation, Missense
Osteochondrodysplasias - genetics
Osteochondrodysplasias - metabolism
Point Mutation
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
R-SNARE Proteins
Sequence Homology, Amino Acid
Transcription Factors
X Chromosome
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Summary:SEDL is an evolutionarily highly conserved protein in eukaryotic organisms. Deletions or point mutations in theSEDL gene are responsible for the genetic disease spondyloepiphyseal dysplasia tarda (SEDT), an X-linked skeletal disorder. SEDL has been identified as a component of the transport protein particle (TRAPP), critically involved in endoplasmic reticulum-to-Golgi vesicle transport. Herein, we report the 2.4 Å resolution structure of SEDL, which reveals an unexpected similarity to the structures of the N-terminal regulatory domain of two SNAREs, Ykt6p and Sec22b, despite no sequence homology to these proteins. The similarity and the presence of unusually many solvent-exposed apolar residues of SEDL suggest that it serves regulatory and/or adaptor functions through multiple protein-protein interactions. Of the four known missense mutations responsible for SEDT, three mutations (S73L, F83S, V130D) map to the protein interior, where the mutations would disrupt the structure, and the fourth (D47Y) on a surface at which the mutation may abrogate functional interactions with a partner protein.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M207436200