The synucleins

Abstract

Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumors. The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. All synucleins have in common a highly conserved alpha-helical lipid-binding motif with similarity to the class-A2 lipid-binding domains of the exchangeable apolipoproteins. Synuclein family members are not found outside vertebrates, although they have some conserved structural similarity with plant 'late-embryo-abundant' proteins. The alpha- and beta-synuclein proteins are found primarily in brain tissue, where they are seen mainly in presynaptic terminals. The gamma-synuclein protein is found primarily in the peripheral nervous system and retina, but its expression in breast tumors is a marker for tumor progression. Normal cellular functions have not been determined for any of the synuclein proteins, although some data suggest a role in the regulation of membrane stability and/or turnover. Mutations in alpha-synuclein are associated with rare familial cases of early-onset Parkinson's disease, and the protein accumulates abnormally in Parkinson's disease, Alzheimer's disease, and several other neurodegenerative illnesses. The current challenge is to understand the normal cellular function of these proteins and how they might contribute to the development of human disease.

Figure 1

Alignment and relationships of the 16 known synuclein sequences. There are about 80 synuclein sequences in GenBank [1], which can be further sorted into 16 unique groups, each representing a single protein-coding sequence orthologous to one of the three synucleins (summarized in Table 1). (a) The resulting 16 synuclein sequences were aligned with the Multalin program [37]. Shading indicates identity with rat α-synuclein; blue bars represent the 11-residue repeats. (b) A dendrogram of synuclein relationships, generated with ClustalW [38] and displayed using TreeView [39].

Figure 2

Comparison of the amphipathic α-helical domains of α-synuclein and related proteins. Sequences of interest were imported into Swiss-PdbViewer [40], assigned an ideal α-helical structure, and exported as .pdb files. Models were then formatted and exported with RASMol [41], and animations (available with the complete version of this article, online) were compiled with QuickTime Pro. (a) Human α-synuclein residues 1-50, modeled as an α-helix. The initial frame shown here shows just the hydrophilic face of the helix, with acidic residues confined to the center (red) and basic residues at each interface (yellow); the opposite hydrophobic face (shown in the animation online) contains only uncharged residues (white). (b) Human apolipoprotein AI residues 190-231; (c) Arabidopsis thaliana LEA76 residues 1-50; (d) C. elegans LEA residues 351-400; all are modeled as in (a).