Biological iron-sulfur clusters: mechanistic insights from mass spectrometry

Iron-sulfur (FeS) clusters are protein cofactors that are ubiquitous in life, performing a wide range of functions, such as in electron transfer, catalysis and gene regulation. This functional diversity is underpinned by the inherent reactivity of FeS clusters towards redox change and reaction with small molecules such as molecular oxygen and nitric oxide. Such reactivity also presents significant challenges for their study, and difficulties in obtaining sufficient quantities of stable, homogenous FeS protein samples have severely hampered progress in understanding these fascinating proteins. Recently, the application of mass spectrometry, under conditions where the cluster cofactor remains protein-associated, has yielded major new insight, particularly into FeS cluster assembly and the chemistry occurring at the FeS clusters of transcriptional regulators that coordinate the cell’s response to changing conditions, such as availability of O2 and cellular iron status, or the onset of oxidative or nitrosative stress. Here we review this recent progress, highlighting the power of native mass spectrometric approaches for studies of protein cofactors.