The eukaryotic cell is highly organized with specific functions and macromolecules distributed to various compartments. One such compartment is the cilium, a hair-like organelle that is found on the surface of almost all cells in the human body where it functions in motility and sensory reception. An increasing number of genetic diseases and syndromes (collectively known as ciliopathies) have in recent years been mapped to genes encoding ciliary proteins. Understanding how the cilium is made and what goes wrong in ciliopathies is thus of vital importance.
In our lab we work on the logistic problem of how macromolecules are specifically targeted to the cilium, a process required for the formation, maintenance and function of cilia. More than 600 proteins are estimated to reside in the cilium and thus require active transport from their site of translation in the cytosol. This process is known as IntraFlagellar Transport (IFT) and relies on molecular motors as well as on a large protein complex (the IFT complex) that is thought to mediate the contacts between motors and ciliary cargoes. Mutations in core IFT proteins commonly lead to the absence of cilia and are lethal at the embryonic stage in knockout mice. It is currently not known how the approximately twenty IFT proteins assemble into large macromolecular complexes that mediate IFT. Our lab aims at elucidating this process by reconstituting and determining molecular structures of IFT complexes. We hope that this line of research will not only expand our knowledge concerning cilium assembly and maintenance but also help to understand the molecular basis for ciliary pathologies.
The lab received a 5-year ERC grant to investigate structural and regulatory aspects of intraflagellar transport (2012-2017)
Published papers by the lab in 2014 include:
Mourão, A., Nager, A.R., Nachury, M.V., and Lorentzen, E., (2014) Structural basis for membrane targeting of the BBSome by ARL6, Nat Struct Mol Biol, doi:10.1038/nsmb.2920
Taschner, M., Kotsis. F., Braeuer, P., Kuehn, W.E., and Lorentzen, E., (2014) Crystal structures of IFT70/52 and IFT52/46 provide insight into intraflagellar transport B core complex assembly, JCB, 207(2):269-282
The following review gives and up-to-date account of IFT complx architecture and cargo interactions: