Department of Chemistry
Ben-Gurion University of the Negev
P.O.B 653 Beer-Sheva
Tel : 972-8-6461195
:1998-2001Ph.D. Technion-Israel Institute of Technology, Department of Chemistry, Haifa, Israel. Advisor: Professor Ehud Keinan, jointly with The Scripps Research Institute, La Jolla, California. Advisor: Professor Phillip Dawson.
:1996-1998M.Sc. Technion-Israel Institute of Technology, Department of Chemistry, Haifa, Israel.
1993-1996: B.Sc. Ben-Gurion University of the Negev, Department of Chemistry, Beer Sheva, Israel.
Research in the Brik group focus on chemical and semisynthesis of Posttranslationally modified protein to stuffy the role of these modifications at the molecular level. Posttranslational modifications play an important role in regulating protein structure and function in health and disease. Ubiquitylation is one example for such a modification wherein both the extent (polyubiquitylation vs mono-ubiquitylation) and the sequence position of this modification dictates the function and fate of the ubiquitylated protein. In the ubiquitylation process three distinct enzymes, known as the E1-E3 system, collaborate to achieve a site-specific tagging of the lysine residue(s) in the target protein. This condensation step generates an isopeptide linkage between the -NH2 of the lysine residue and the activated C-terminal glycine of ubiquitin (Ub). The overwhelming majority of studies in the field rely on the in vitro enzymatic reconstitution of this complex posttranslational modification for the protein of interest. However, this process is often challenged by the heterogeneity of the modified protein, the isolation of the specific ligase (E3) and obtaining reasonable quantities of the ubiquitinated protein. We have recently reported the developments of highly efficient and site-specific peptide and protein ubiquitination utilizing thiolysine. Moreover, we were able to achieve the chemical synthesis of ubiquitin thioester as a key intermediate in the ubiquitination process. This battery of chemical tools allowed for the first semi-synthesis of homogeneous ubiquitinated alpha-synuclein to support the ongoing efforts aiming at studying the effect of ubiquitination in health and disease. In addition, the total chemical synthesis of all Lys-linked di-ubiquitin chains as well as the K48-linked tetra-ubiquitin, composed of 304 amino acids, was also achieved. More recently, the synthesis of ubiquitinated peptides linked to mono-, di-, tri-, and tetra-ubiquitin (K48 and K63) was also made possible, which enabled us to examine the behavior of these novel bioconjugates with several deubiquitinases.