Dr Shehab Ismail
Structural Biology of the Cilia Lab
Beatson Institute for Cancer Research
The primary cilium is a microtubule-based sensory organelle that is present on almost all cell types in the body. The assembly of cilia is tightly synchronised with cell cycle and coordinates several signalling pathways such as the Wnt and Hedgehog pathways, both of which are therapeutic targets for cancer. Defects in the structure or function of cilia result in a copious spectrum of diseases collectively called ciliopathies. Phenotypes include retinal degeneration, renal cysts, intellectual disabilities, obesity, polydactyly and infertility.
Concentrating signalling proteins and receptors inside the cilium is key to its function. Nevertheless the cilium, unlike other organelles, is not separated from the cell body by a membrane barrier and the molecular mechanism for regulating ciliary targeting and access of relevant protein to cilia is elusive. A combination of ciliary targeting and the existence of a diffusion barrier that is found at the base of the cilium are believed to play a role in this process. In our group we try to unravel the regulation of ciliary access by using an interdisciplinary approach where we combine structural biology, biochemistry and cell biology.
Key Recent Publications
- Fansa EK, Kösling SK, Zent E, Wittinghofer A, Ismail S. PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nat Commun 7, 11366, 2016. doi: 10.1038/ncomms11366
- Zimmermann G*, Papke B*, Ismail S*, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PIH, Waldmann H. Small Molecule Inhibition of the Kras-PDEδ Interaction Impairs Oncogenic Kras Signaling. Nature 497:638-42, 2013 *authors contributed equally
- Wätzlich D, Vetter I, Gotthardt K, Miertzschke M, Chen Y-X, Wittinghofer A, Ismail S. The interplay between RPGR, PDEδ and Arl2/3 regulates the ciliary targeting of farnesylated cargo. EMBO Rep. 14:465-72, 2013
- Ismail SA, Chen Y-X, Miertzschke M, Vetter I, Carolin K, Wittinghofer A. Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. EMBO J. 31:4085-94, 2012
- Ismail SA, Chen Y-X, Rusinova A, Chandra A, Bierbaum M, Gremer L, Triola G, Waldmann H, Bastiaens PIH, Wittinghofer A. Arl2 and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo. Nat Chem Biol. 7:942-9, 2011
- Ismail SA, Vetter IR, Sot B, Witinghofer A. The structure of an Arf-ArfGAP complex reveals a Ca2+ regulatory mechanism. Cell 141:812-21, 2010