University of Toronto Biochemistry

	Frank Sicheri Professor Ph.D., McMaster University, 1994 PDF, Rockefeller University, New York, 1997
	Samuel Lunenfeld Research Institute Mount Sinai Hospital 416-586-8471 sicheri@lunenfeld.ca

Structural Biology of Eukaryotic Signal Transduction

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Research Synopsis

Our research is directed at understanding protein kinase regulation with a focus towards the underlying structural mechanisms that imparts specificity to signaling function. Using x-ray crystallography, we seek to uncover the structural basis for catalytic switching, substrate recognition and down-stream phospho-regulatory mechanisms. In addition, we are interested in uncovering the structure and function of novel effectors that impact on protein kinase function. These efforts have led our lab into the area of ubiquitin directed proteolysis. Our long-term goal is to make use of what we learn to develop drugs to treat human disease.

Crystal structure of Cdc34 bound to the small molecule inhibitor CC0651

Selected Publications

To see a complete list of publications please visit pubmed:

Ceccarelli DF, Tang X, Pelletier B, Orlicky S, Xie W, Plantevin V, Neculai D, Chou YC, Ogunjimi A, Al-Hakim A, Varelas X, Koszela J, Wasney GA, Vedadi M, Dhe-Paganon S, Cox S, Xu S, Lopez-Girona A, Mercurio F, Wrana J, Durocher D, Meloche S, Webb DR, Tyers M, Sicheri F . An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. (2011) Cell . 145(7):1075-87.

Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, O'Donnell L, Kumakubo A, Munro M, Sicheri F , Gingras AC, Natsume T, Suda T, Durocher D. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. (2010) Nature, 466(7309):941-6.

Orlicky S, Tang X, Neduva V, Elowe N, Brown ED, Sicheri F , Tyers M. An allosteric inhibitor of substrate recognition by the SCF(Cdc4) ubiquitin ligase. (2010) Nat Biotechnol . (7):733-7.

Rajakulendran T, Sahmi M, Lefrançois M, Sicheri F, Therrien M. A dimerization-dependent allosteric mechanism drives RAF catalytic activation. (2009) Nature, 461, 542-5.

Mao DYL, Neculai D, Downey M, Orlicky S, Haffani Y, Ceccarelli DF, Ho JSL, Szilard RK, Zhang W, Ho CS, Wan L, Fares C, Rumpel S, Kurinov I, Durocher D, Sicheri F. Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine. (2008) Molecular Cell, 32, 259-75.

Kurz T, Chou Y-C, Willems A, Meyer-Schaller N, Hecht M-L, Tyers M, Peter M, Sicheri F. Dcn1 Functions as a Scaffold-Type E3 Ligase for Cullin Neddylation (2008) Molecular Cell, 29, 23-35.

Lee K, Dey M, Neculai D, Cao C, Dever TE, Sicheri F. Structure of the Dual Enzyme Ire1 Reveals the Basis of Catalysis and Regulation in Nonconventional RNA Splicing. (2008) Cell, 132, 89-100.

Wiesner S, Ogunjimi AA, Wang HR, Rotin D, Sicheri F, Wrana JL, Forman-Kay JD. Autoinhibition of the HECT-Type Ubiquitin Ligase Smurf2 through Its C2 Domain. (2007) Cell, 30, 651-62.

Tang X, Orlicky S, Lin Z, Willems A, Neculai D, Ceccarelli DF, Mercurio F, Shilton BH, Sicheri F, Tyers M. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. (2007) Cell, 129, 1165-1176.

Department of Biochemistry
University of Toronto
Toronto, Canada

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