Illuminating human Fe-S cluster biology

Ziel

Iron-sulfur (Fe-S) clusters were ancient partners in the origin of life- spontaneously formed in the anaerobic primordial oceans, they likely helped catalyze carbon fixation and rudimentary metabolism. Highly versatile, Fe-S clusters unlock previously inaccessible abilities for their binding proteins, aiding in electron relay, catalysis, regulation, and structural stability. Over the past 20 years, it has become clear that Fe-S clusters must be formed de-novo within the cell by essential proteinaceous machineries and relayed directly to their binding proteins. During this time, huge strides have been made to delineate the components and molecular mechanisms of this pathway. However, our grasp of the regulation, client range and dynamics of Fe-S cluster biosynthesis in the human cell remains fragmented. These critical gaps of knowledge hinder our understanding of how Fe-S cluster biosynthesis supports healthy human cells and how its breakdown can lead to multiple diseases.
We aim to break through to a new level understanding of human Fe-S cluster biosynthesis– catapulting our knowledge forward to encompass its holistic cellular state. In FeSurveil, we will broadly and unbiasedly identify the human Fe-S cluster proteome (Aim 1), uncover regulators of Fe-S cluster biosynthesis (Aim 2), and dissect client priorities for the relay proteins (Aim 3). FeSurveil will leverage our expertise in Fe-S cluster biology and capitalize on our unique interdisciplinary skills, spanning tool creation, state-of-the-art genetic profiling, proteomic analysis, cell biology and biochemical approaches. Together, these independent but synergistic lines of research will illuminate the complex reciprocal relationship between Fe-S cluster biosynthesis and the dynamic cellular environment. This comprehensive perspective is essential for understanding fundamental aspects of human Fe-S cluster biology, while also providing valuable information for disease intervention and bioengineering.