Titre : Organic Chemistry Applied to Proteins: The Case of Ubiquitination and Deubiquitination
Cette conférence sera prononcée (en anglais) par le Professeur Ashraf Brik de la Faculté de chimie de la Technion-Israel Institute of Technology.
Résumé:
In this talk, I will present our synthetic approaches for protein ubiquitination to shed light on the various unknown aspects of the ubiquitin signal in cellular pathways. The enzymatic attachment of ubiquitin to a specific protein target is a widely utilized posttranslational modification in cellular functions and has been implicated in several diseases. The majority of biochemical, biophysical and structural studies in the field rely on the in vitro enzymatic reconstitution of this complex modification for the protein of interest. However, the enzymatic approaches are often challenged by difficulties in obtaining the ubiquitinated conjugates in acceptable homogeneity and workable quantities. Our group has been developing novel chemical approaches for the efficient and site-specific protein ubiquitination to overcome these limitations. Our methods combine state of the art peptide ligation approaches and the use of Pd(II) complexes for the assembly of these challenging proteins starting from commercially available amino acids. These approaches allowed for the preparation of ubiquitinated protein such as alpha-synuclein and histone H2B to support the ongoing efforts aiming at studying the effect of ubiquitination in these systems. We are also expanding these approaches to study and target important deubiquitinases, which reverse the ubiquitination step, to shed light on their role in health and disease and ultimately for drug development.
- Sumeet Singh, Indrajit Sahu, Sachitanand Mali, Hosahalli Hemantha, Oded Kleifeld, Michael H Glickman and Ashraf Brik; Synthetic uncleavable ubiquitinated proteins dissect proteasome deubiquitination and degradation, and highlight distinctive fate of tetraubiquitin, Journal of American Chemical Society, 2016, 138,16004.
- Muhammad Jbara, Suman Kumar Maity, Mallikanti Seenaiah and Ashraf Brik, Palladium Mediated Rapid Deprotection of N-terminal Cysteine Under Native Chemical Ligation Conditions for the Efficient Preparation of Synthetically Challenging Proteins, Journal of American Chemical Society, 2016, 138, 5069.
- Michael Morgan, Mahmood Haj-Yahya, Alison E. Ringel, Prasanthi Bandi, Ashraf Brik and Cynthia Wolberger, Structural Basis for Histone H2B deubiquitination by SAGA DUB Module, Science, 2016, 351,725.
- Muhammad Jbara, Suman Kumar Maity, Michael Morgan, Cynthia Wolberger and Ashraf Brik: Total Chemical Synthesis of Phosphorylated Histone H2A at Tyr57 Reveals Insight into the Inhibition Mode of the SAGA Deubiquitinating Module, Angewandte Chemie Int. Ed. 2016, 55, 4972.
- Somasekhar Bondalapati, Emad Eid, Sachitanand M. Mali, Cynthia Wolberger, Ashraf Brik, Total Chemical Synthesis of SUMO-2-Lys63-linked Diubiquitin Hybrid Chains Assisted by Removable Solubilizing Tags, Chemical Science, 2017, 8, 4027-4034.
