Dr Shabih Shakeel - Structural Biology division

Dr Shabih Shakeel - Structural Biology division

Location: 
Davis Auditorium
Start Time: 
Wed, 05/05/2021 - 1:00pm
End Time: 
Wed, 05/05/2021 - 2:00pm

WEHI Wednesday Seminar hosted by Matthew Call & Peter Czabotar

 

Dr Shabih Shakeel

Laboratory Head, Structural Biology division - New Medicines & Advanced Technologies Theme


 

Structures of Protein Complexes Involved in Fanconi Anemia DNA Repair

 

Davis Auditorium

Online access via Slido
https://sli.do and enter code #WEHIWEDNESDAY

Including Q&A session

 

The Fanconi Anemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks. Genetic inactivation of this pathway impairs development, prevents blood production and promotes cancer. The key molecular step in the FA pathway is the monoubiquitination of a heterodimer of the FANCD2-FANCI (D2-I) substrate proteins by the FA core complex - a megadalton multiprotein E3 ubiquitin ligase. Monoubiquitinated FANCD2-FANCI (ubD2-I) then initiates removal of the DNA crosslink. Lack of molecular insight into the FA core complex and ubD2-I limits a detailed explanation of how this DNA repair pathway functions. The FA core complex contains eight different subunits, most with unknown structure and no substantial homology to proteins of known structure. Moreover, the functions of many of the subunits are unclear. Shabih aimed to understand the mechanism of the FA core complex by biochemically reconstituting the specific monoubiquitination reaction, and by determining structures of the FA core complex and its product, ubD2-I. He now reports purification and structural characterization of an intact FA core complex and ubD2-I. Together his data allowed him to propose a model for the architecture of the entire FA core complex, providing new insight into the structure and function of its subunits and how its E3 ligase activity leads to remodelling of D2-I into a DNA clamp.

 

Shabih Shakeel studied Biotechnology and Bioinformatics in India and received his PhD from University of Helsinki in Finland, working with Prof Sarah Butcher. He was then a post-doc at the MRC Laboratory of Molecular Biology in Cambridge with Lori Passmore. Both his PhD and post-doctoral work focused on the structure and function of large macromolecular assemblies using cryoEM. Since 2021, he has been a Laboratory Head at WEHI and Principal Research Fellow at the Department of Biochemistry and Pharmacology, University of Melbourne. His current work focuses on understanding the mechanisms of macromolecular protein complexes involved in regulating gene expression. He uses an integrated approach combining structural, biochemical, and functional studies, aiming to reconstitute multi-protein complexes and their activities, and determine their high-resolution structures to understand their mechanisms.