egeorges_lab

Functional ABC transporters encode two cytoplasmic domains, a cytoplasmic nucleotide binding domain(s) (e.g., NBDs, each containing one ABC signature sequence) and two transmembrane domains (e.g., TMDs, each encoding six transmembrane helices). Some ABC transporters contain an additional domain termed, Linker Domain(s) (e.g., L1, or L0 and L1). The NBDs are thought to energize the transport functions of ABC proteins, through conformational changes of the TMD helices, the TMDs are believed to encode their ligand binding sites and determines their substrate specificities. The function(s) of the linker domains remains a matter of speculation and is currently unknown. Interestingly, while the NBD shares the highest sequence identity between different ABC transporters and across different species, the Linker domains share NO sequence identity, are highly charges and encode several phosphorylation sites. Moreover, although high-resolution crystal structure of several ABC transporters have been resolved, it has NOT been possible to determine the structure of the linker domain as it encodes disordered structure. It is interesting to note that disordered structures are normally involved in protein-protein interactions, whereby such protein interactions are modulated by post-translational modification.

In one example, we have identified specific sequences in ABCC1 linker domain that bind with high affinity to tubulin dimer. Phosphorylation of these interacting sites inhibited their binding to tubulin. Interestingly, the same sites in ABCC1 linker domain interact with ATP-synthase alpha, but only when these sites are phosphorylated.

It will be of interest to know if the same domains of other ABC transporters also bind to the same or different proteins. Moreover, how these protein interactions affect their sub-cellular localization, half-lives and functions.