NSF-BSF: Unraveling the molecular determinants of protein oligomerization

Since most biological functions can only be described using a system of interacting protein molecules, many of which oligomerize into homomers, uncovering the molecular and evolutionary mechanisms of homo-oligomerization is particularly important. We envision that the proposed research will advance our understanding of the structural, biophysical, and cellular mechanisms of formation and regulation of homo-oligomeric complexes in the living cell. It will also unveil the evolutionary mechanisms of bacterial adaptation via tuning the properties of homo-oligomeric interfaces and cellular systems that modulate the intracellular activity and turnover of homo-oligomers to the particular environmental needs. Our primary objective is fundamental insights into protein structure/function relationships; however, our findings will likely have longer-term practical implications in (I) enzyme engineering, and (ii) development of antimicrobial substances. De novo design of enzymes whose intracellular properties can be controlled via cellular networks is still a largely unmet challenge. Understanding how the properties of the interfaces control the intracellular activity and turnover of homo-oligomeric enzymes can be harnessed for the generation of new enzymes in the laboratory. Further, development of small molecules that specifically target and interfere with assembly or disassembly of homo-oligomeric enzymes essential to bacterial fitness and adaptation can help to manage bacterial infections.