Structural biology of BEACH-containing proteins

Columbia Univ New York Morningside, New York NY

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Abstract

DESCRIPTION (provided by applicant): The BEACH domain is highly conserved among a large family of eukaryotic proteins, and is crucial for their functions in vesicular transport, membrane dynamics and receptor signaling. Members of this family include mammalian CHS, Neurobeachin (Nbea), FAN and LBA, Drosophila AKAP550, Dictyostelium LvsA, and C. elegans F10F2.1. The CHS protein may be involved in the trafficking of lysosomes, melanosomes and other vesicles. The human disease Chediak-Higashi syndrome is caused by non-sense and frame-shift mutations in the CHS gene, leading to premature termination of the CHS protein product and the loss of the BEACH domain. Nbea has been implicated in membrane traffic in neuronal cells. LBA may have a function in polarized vesicle trafficking, and is localized to vesicles after stimulation by lipopolysaccharide (LPS) in macrophages. FAN mediates signaling by the p55 tumor necrosis factor receptor in the activation of downstream neutral sphingomyelinase as well as apoptosis. The functional importance of the BEACH-containing proteins is also underscored by the fact that most genomes carry more than one copy of these proteins. For example, there are eight BEACH-containing proteins in the human genome, 5 in Drosophila, 3 in C. elegans, and 6 in the plant Arabidopsis. Despite their important roles in vesicle trafficking and receptor signaling, no structural information is currently available on any of these proteins. Moreover, the exact functions of these proteins, and the structural basis for their functions, are currently unknown. Furthermore, the amino acid sequences of these proteins are generally unique and do not share homology to other proteins in the database. This makes it virtually impossible to infer the biological functions solely from sequence analysis. To fill this gap in our knowledge, we have recently determined the crystal structure of the BEACH domain, and carried out preliminary biochemical and functional studies to assess the information from the structures. These initial results set the stage for further biochemical, biophysical, and functional studies of this important family of proteins.