Abstract
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.
Highlights
BBS9 is a component of the octameric Bardet-Biedl syndrome protein complex (BBSome), a complex that transports membrane proteins to the primary cilium
Structure of the HsBBS91–407 N-terminal Domain—To structurally characterize H. sapiens BBS9, we recombinantly expressed the protein in E. coli
Despite knowing that HsBBS91–407 likely adopts a -propeller fold, we found no molecular replacement solutions using various -propeller templates
Summary
BBS9 is a component of the octameric BBSome, a complex that transports membrane proteins to the primary cilium. Despite being continuous with the plasma membrane, the membrane of the primary cilium has a unique composition of proteins, namely an enrichment of specific G-protein-coupled receptors involved in signaling [1, 3] How this organelle maintains the integrity and specificity of its compartment remains an active area of investigation, a septin diffusion barrier has been shown to play a critical role [4, 5]. Given the structural homology to vesicle coat proteins on a domain level, we set out to assess whether and to what degree this homology held true on the atomic level To this end, another group has already reported the first high-resolution crystal structure of a BBS protein, the BBS1 N-terminal -propeller from Chlamydomonas reinhardtii in complex with the. BBS9 knockdown in zebrafish leads to defects in ciliogenesis and neuronal development that the G141R mutant fails to rescue [14]
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