Professor and HHMI Investigator
Ph.D., The Weizmann Institute of Science, 1991
Structural biology; nucleic acid regulation; RNAi; molecular recognition; X-ray crystallography
We study the molecular basis of cell regulatory processes by using the tools of structural biology and biochemistry to examine proteins and protein complexes associated with these processes. Our efforts largely center on nucleic acid regulatory processes.
The introduction of double-stranded RNA into a cell can trigger a gene silencing process called RNA interference (RNAi). Although there has been remarkable progress in unraveling the components of the RNAi machinery, we are just beginning to understand how they work at the molecular level. Therefore, we embarked on structural and biochemical studies of these proteins. By solving the structure of a full-length Argonaute protein, a key component in the RNAi machinery, we identified Argonaute as “Slicer”, the enzyme that cleaves the mRNA as directed by the siRNA. These studies enhance our understanding of this pathway, and should also improve the use of RNAi as a tool for gene knockdown technology.
Another system is DNA replication initiation in papillomaviruses. Papillomaviruses are DNA tumor viruses that cause benign and malignant lesions in humans. To gain insight into the mechanism of replication initiation, we are studying two viral proteins that are required for viral replication, the initiator E1 and the transcription factor E2, and their complexes. Based on crystal structures of the E1 hexameric helicase in complex with nucleotide and ssDNA as well as structures of DNA complexes of the DNA-binding domain, we presented a strand exclusion mechanism by sequential ATP hydrolysis for helicase activity of the initiator. This mechanism has wide implications for many oligomeric ATPases.
Please visit Leemor's Lab home page.
Ipsaro*, J.J., A.D. Haase*, A.D., Knott, S.R., Joshua-Tor, L.** and Hannon, G.J. **2012. The structural biochemistry of Zucchini implicates it as a nuclease in piRNA biogenesis. Nature 491: 279–283.
Elkayam, E. Kuhn, C.-D., Tocilj, A., Haase, A.D., Greene, E.M., Hannon, G.J. and Joshua-Tor, L. 2012. The structure of human Argonaute-2 in complex with miR-20a. Cell 150: 100–110.
Schalch, T., Job, G., Shanker, S., Partridge, J.F. and Joshua-Tor, L. 2012. The Chp1-Tas3 core is a multifunctional platform critical for gene silencing by RITS. Nat. Struct. Mol. Biol. 18: 1351–1357.
Lavy, T., Kumar, P.R., He, H. and Joshua-Tor, L. 2011. The Gal3p transducer of the GAL regulon interacts with Gal80p repressor in its ligand-induced closed conformation. Genes & Dev. 26: 294–303.
Enemark, E.J. and Joshua-Tor, L. 2006. Mechanism of DNA translocation in a replicative hexameric helicase. Nature 442: 270–275.