Stoddard Lab

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This week, we profile a recent publication in Structure from Betty Shen (pictured, second from right)
in the lab of Barry Stoddard (pictured, third from left) at Fred Hutch.

Can you provide a brief overview of your lab’s current research focus?
We work at the intersection of (i) protein biophysics, structure, and engineering and (ii) microbiology. For the former, we are interested in how the information found in the three-dimensional, atomic-resolution structure of a protein can be used to alter or reprogram its behavior and function, or to create entirely new protein folds and functions altogether. We are also interested in the best possible combination of approaches to carry out such experiments. For the latter, we are primarily interested in the mechanisms by which bacterial defend themselves from viral infection and the corresponding mechanisms by which those same viruses achieve resistance against bacterial defense mechanisms. The ‘arms race’ between bacteria and viruses (which are called ‘phage’) probably represents one of the longest-running biological conflicts in the history of life.

What is the significance of the findings in this publication?
Just like a human immune system, the forms of immunity found in bacteria that defend them against foreign invaders must be able to distinguish between ’self’ and ’nonself’, and also must be able to rapidly adapt towards new infectious threats. One particularly well-known form of bacterial anti-viral immune system is referred to as a ‘restriction-modification (‘RM’) system; such systems destroy invading viral DNA while protecting bacterial DNA from the same fate. Some RM systems put both activities on a single protein molecule and are then able to ensure that protection versus destruction is correctly aimed at self and non-self DNA, respectively. Our study demonstrates, for one particular type of ‘RM’ system (the DrdV restriction-modification enzyme) how that is accomplished.

What are the next steps for this research?
‘RM’ systems that combine protective and destructive activities into single protein molecules or protein assemblies come in many different flavors and organizations. We would like to examine the same question for a very different type of RM enzyme and compare that answer to the one we just determined for DrdV.

Beyond that, there are many, much more complicated, forms of viral defense systems found in bacteria (beyond ‘RM’ systems) for which we have little understanding of their mechanism. We are in the early stages of working out the details of one such system, that relies on the combined activities of seven (7!) different protein factors to defend against viral infection.

This work was funded by:

The National Institute of General Medical Sciences (NIGMS, which is part of the NIH), the Fred Hutchinson Cancer Research Center, the University of Washington Institute for Protein Design, New England Biolabs, and the Washington State Life Sciences Research Foundation.

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