Structural Characterization of Bardet-Biedl Syndrome 9 Protein (BBS9)

• Published in: The Journal of biological chemistry Vol. 290; no. 32; pp. 19569 - 19583
• Main Authors: Knockenhauer, Kevin E., Schwartz, Thomas U.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.08.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; analytical ultracentrifugation; Bardet-Biedl Syndrome - metabolism; chromatography; cilia; crystal structure; Crystallography, X-Ray; Cytoskeletal Proteins; Escherichia coli - genetics; Escherichia coli - metabolism; Gene Expression; genetic disease; Humans; Models, Molecular; Molecular Biophysics; Molecular Sequence Data; Mutation; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Protein Folding; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Stability; Protein Structure, Secondary; protein translocation; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sequence Alignment; Structural Homology, Protein; crystal structure; analytical ultracentrifugation; cilia; genetic disease; chromatography; protein translocation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.649202

The Bardet-Biedl syndrome protein complex (BBSome) is an octameric complex that transports membrane proteins into the primary cilium signaling organelle in eukaryotes and is implicated in human disease. Here we have analyzed the 99-kDa human BBS9 protein, one of the eight BBSome components. The protein is composed of four structured domains, including a β-stranded N-terminal domain. The 1.8 Å crystal structure of the 46-kDa N-terminal domain reveals a seven-bladed β-propeller. A structure-based homology search suggests that it functions in protein-protein interactions. We show that the Bardet-Biedl syndrome-causing G141R mutation in BBS9 likely results in misfolding of the β-propeller. Although the C-terminal half of BBS9 dimerizes in solution, the N-terminal domain only does so in the crystal lattice. This C-terminal dimerization interface might be important for the assembly of the BBSome. Background: BBS9 is a component of the octameric BBSome, a complex that transports membrane proteins to the primary cilium. Results: BBS9 has four folded domains, based on structure prediction; the N-terminal domain is a β-propeller. Conclusion: BBS9 likely acts as a scaffold component in the BBSome coat. Significance: The structural data help in understanding a mutation that causes Bardet-Biedl syndrome.