Fe-S clusters masquerading as zinc finger proteins.

Metal ions are commonly found as protein co-factors in biology, and it is estimated that over a quarter of all proteins require a metal cofactor. The distribution and utilization of metals in biology has changed over time. As the earth evolved, the atmosphere became increasingly oxygen rich which affected the bioavailability of certain metals such as iron, which in the oxidized ferric form is significantly less soluble than its reduced ferrous counterpart. Additionally, proteins that utilize metal cofactors for structural purposes grew in abundance, necessitating the use of metal co-factors that are not redox active, such as zinc. One common class of Zn co-factored proteins are zinc finger proteins (ZFs). ZFs bind zinc utilizing cysteine and histidine ligands to promote structure and function. Bioinformatics has annotated 5% of the human genome as ZFs; however, many of these proteins have not been studied empirically. In recent years, examples of annotated ZFs that instead harbor Fe-S clusters have been reported. In this review we highlight four examples of mis-annotated ZFs: mitoNEET, CPSF30, nsp12, and Fep1 and describe methods that can be utilized to differentiate the metal-cofactor.