This week we profile a recent publication in Nature Chemical Biology from the lab of
Dr. Sophie Helaine (pictured, right) at Harvard Medical School with first author Dr. Grzegorz Grabe (left).
Can you provide a brief overview of your lab’s current research focus?
The Helaine Lab focuses on studying antibiotic persistence and mechanisms of growth arrest in bacteria. Many bacteria live a growth arrested life, particularly when they are facing stresses such as those mounted against pathogens by host immune cells. In this growth arrested state, bacteria display remarkable properties and features that allow them to withstand attacks from their environment, including antibiotic exposure. Using Salmonella Typhimurium as a model organism, we decipher the molecular mechanisms of survival of the growth arrested pathogen and its interaction with its host. Toxin-antitoxin systems are fascinating protein complexes that hold the ability to trigger growth arrest in their bacterial host when the toxin is liberated but their roles, activation and mode of action remain elusive. We employ structural biology, biochemistry, next-generation sequencing and infection models to decipher their impact on Salmonella.
What is the significance of the findings in this publication?
Toxin-Antitoxin (TA) systems encode non-secreted toxins and antitoxins that pair with high specificity, even when several homologous copies are present per genome. We determined the crystal structures of the three TacAT complexes of Salmonella Typhimurium to understand the structural basis of such specific pairing. Alteration of a discrete structural add-on element on the toxin drives specific recognition by their cognate antitoxin. The region supporting toxin-antitoxin specific pairing is key to neutralization and our work reveals that additional toxin-antitoxin interfaces increase the safe space for evolution of pairing specificity. This work visits how protein-protein interfaces that serve both binding specificity and protein functionality can diverge through mutations without compromising function, with the support of auxiliary interfaces.
What are the next steps for this research?
There is still a lot to be elucidated about TAs in general. A direct next step for this research is to assess whether additional toxin-antitoxin interfaces also act as elements supporting neutralization in other TA families and, by extension, evolution of specificity in other protein complexes. We are also currently investigating the different steps of regulation of expression of the TacAT systems and the consequences of natural activation of the toxins during the Salmonella life cycle.
