Seminar | IMB Seminar

Evolution of SLiM-mediated Interactions and their Hijack by Viral Pathogens

Dr Lucía Chemes (Universidad Nacional de San Martín (UNSAM), Buenos Aires, Argentina)


Short linear motifs (SLiMs) are protein-protein interaction modules found within intrinsically disordered protein regions (IDRs) that mediate signal transmission in eukaryotic signaling networks. Because they are encoded by a few key residues, SLiMs can appear de novo by convergent evolution, and are extensively mimicked by pathogens to hijack host cells. Within IDRs, several SLiMs can be tethered by flexible linkers increasing the avidity and affinity of SLiM-mediated interactions. Viral proteins are under strong selection pressure to subvert host cell function, and we used the disordered adenovirus E1A and papillomavirus E7 viral proteins as model systems to study the evolution of binding and tethering functions in IDPs. Viral SLiMs evolve quickly and SLiMs that bind to the same partner show correlated evolutionary patterns, suggesting IDR evolution is coupled over large distances. Changes in SLiMs are associated with viral evolutionary events, suggesting that motif gains and losses underlie viral adaptation. Using the E1A protein as a model system, we demonstrated that two SLiMs tethered by a flexible linker evolved to optimize the binding affinity of E1A for a host factor. We identify a molecular mechanism that optimizes tethering across a large family of poorly conserved E1A linkers by allowing compensatory changes in linker sequence composition and length that preserve IDR dimensions. These studies elucidate how viral proteins use IDRs to optimize binding and tethering functions, enabling an efficient hijack of the host machinery. The mechanisms we identify in viral IDPs explain the conservation of functions in variable IDRs and may underlie the evolution of many disordered protein regions. Current efforts in the lab are focused on the proteome-wide discovery of SLiMs mediating cell cycle regulation by using Proteomic Peptide Phage Display (ProPD).

Date: 29 Jun 2023
Time: 12:00 - 13:00
Location: IMB
Institution: Universidad Nacional de San Martín (UNSAM), Buenos Aires, Argentina
Contact: events(at)