Authors

G Deak¹; H Wapenaar¹; G Sandoval¹; R Chen¹; M Taylor¹; H Burdett¹; J Watson¹; M Tuijtel¹; S Webb¹; MD Wilson¹;  ¹ Wellcome Centre for Cell Biology, University of Edinburgh, UK

Discussion

Trypanosoma brucei is a parasitic kinetoplastid that causes severe disease in both humans and livestock animals. Contrary to model eukaryotes, histone sequences in T. brucei are highly divergent. However, the structural and functional consequences of their variation on chromatin-based processes are unknown. We determined the cryo-EM structure of the T. brucei nucleosome core particle (NCP). Intriguingly, the histone fold architecture of the NCP is mostly conserved but specific sequence alterations lead to distinct DNA and protein interaction interfaces. The T. brucei NCP is unstable and has weakened binding to entry/exit nucleosome DNA but exhibits a novel compensation mechanism via its H2A-H2B dimer interface. The acidic patch in T. brucei has altered topology and is refractory to known binders, indicating that critical chromatin interactions may be altered in this parasite. Phylogenetic analysis and modelling reveal that a majority of our findings are also conserved in other pathogenic Kinetoplastids, opening avenues for multi-target drug discovery. Overall, our results provide a detailed molecular basis for understanding Kinetoplastid chromatin structure and regulation at the mononucleosome level.