Featured Article - April 2010
Short description: A genomic, phylogenetic and structural study hints that these kinases have functional roles that might be druggable.
Anthrax, an acute and often lethal disease, is caused by the bacterium Bacillus anthracis. Bacilli and related species are able to survive for years in harsh conditions by forming spores that are extremely resistant to heat, chemicals, desiccation and other environmental hazards. Yet, when the environment becomes more favourable — when the spores enter the human body, for example — they can germinate rapidly.
The coat of the spore must keep out harmful agents but allow the nutrients through to trigger germination, and so its structure is of considerable interest. A typical spore coat is composed of more than 70 different proteins, and a recent study by Gerard Manning and colleagues from the Salk Institute for Biological Studies, La Jolla, in collaboration with PSI JCSG suggests that a family of kinases, the bacterial spore kinases (BSKs), present in the coat has both catalytic as well as structural roles.
The BSKs are a new subfamily within the CAKs, a family of kinases that mainly phosphorylate small molecules. The BSKs are mostly restricted to spore-forming bacteria, indicating that their role is likely specific to the coat. Considering the important role of spore structures in pathogenesis, and the success of other kinase inhibitors in drug trials, these are potentially important drug targets.
PSI JCSG solved the crystal structure of one of the BSKs, YtaA from B. subtilis, at 2.5 Å. YtaA has a protein kinase-like fold, similar to other CAKs. Comparison to two previous CAK structures shows that, unlike protein kinases, each of these binds ATP in a distinct manner, perhaps to optimise the phosphorylation of individual small molecule substrates.
A combination of structural and comparative genomic analysis showed that YtaA strongly conserves the active site residues of the kinase family, indicating that it not only looks like a kinase, but almost certainly is a kinase. A likely substrate-binding site was also found as a highly conserved patch similar to the substrate-binding regions of other CAKs. A similar analysis showed that other classes of BSK had related but distinct substrate-binding regions, and that many were catalytically inactive pseudokinases, showing that at least some of this family have an important non-catalytic role.
Interestingly, when the protein sequences of the predicted active BSKs were compared with the predicted pseudokinases, a highly conserved, hydrophobic linker was identified that is likely to be linked to enzymatic activity. This linker connects two kinase lobes together and is probably important for stabilizing the protein for proper enzymatic function.
E. D. Scheef et al. Genomics, evolution, and crystal structure of a new family of bacterial spore kinases.
Proteins (2009). doi:10.1002/prot.22663