INTRAFLAGELLAR TRANSPORT - ESBEN LORENTZEN
The eukaryotic cell is highly organized with specific functions and macromolecules distributed to membrane-enclosed compartments also known as organelles. One such organelle, the cilium, is found on almost all cells in the human body where it is responsible for 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 my lab we work on the logistic problem of how to specifically target macromolecules to the cilium. More than 600 proteins are estimated to function in the cilium and all of these proteins are made in the cell body and thus need to be actively recruited to the cilium. 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 a large macromolecular complex that mediates the transport of proteins to the cilium. Our lab aims to shed light on 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 some ciliary pathologies.
NEWS:
The lab recently received the EMBO young investigator award 2012-2014
Published papers by the lab in 2011 include:
Bhogaraju, S., Taschner, M., Morawetz, M., Basquin, C. and Lorentzen, E., EMBO J (2011)
Crystal structure of the intraflagellar transport complex 25/27.
The paper describes the first crystal structure of a complex between the two intraflagellar transport proteins IFT25 and IFT27. In addition to the structure characterization of the calcium-binding IFT25 and the small GTPase IFT27, the paper presents a detailed biochemical and biophysical analysis of nucleotide binding affinities and GTPase activity of WT and mutant IFT27.
Taschner, M., Bhogaraju, S., Vetter M., Morawetz, M., and Lorentzen, E., JBC (2011)
Biochemical mapping of interactions within the intraflagellar transport (IFT) B core complex:
IFT52 binds directly to four other IFT-B subunits.
A biochemical mapping of the protein-protein interactions of the octameric IFT-B complex including the identification of novel interactions and a dissection of domains mediating binding between proteins within the complex.
The following review gives and up-to-date account of the structure and function of IFT proteins in ciliogenesis:
Taschner, M., Bhogaraju, S., and Lorentzen, E., DIFFERENTIATION (2011)
Architecture and function of IFT complex proteins in ciliogenesis.
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