Knowledge Bank

Fe-S clusters are prosthetic groups found in several metalloproteins, and are conserved across all kingdoms of life (Lill, 2008). These clusters have essential yet diverse roles in the mechanics of the cell, including electron transfer, regulation of gene expression, and disulfide reduction (Johnson, 2005). Mutations in cluster-assembly and transfer proteins dramatically affect several crucial metabolic pathways (Ahting, 2015). Genetic mutations to a specific subset of mitochondrial cluster-delivery proteins are broadly categorized as a Multiple Mitochondrial Dysfunction Syndrome (MMDS), and symptoms include impairment of neurological development, lactic acidosis, failure to thrive, and ultimately early death (Invernizzi, 2014) (Navarro-Sastre, 2011). Multiple Mitochondrial Dysfunction Syndrome 1 (MMDS1) arises as a result of the missense mutation c.622G>T in NFU1, a cluster scaffold protein, which mutates a glycine near the Fe-S cluster binding pocket to a cysteine (G208C) (Navarro-Sastre, 2011). The connection between the mutation in NFU1 and MMDS1 has been recently discovered, and at this point, little is known about the role of NFU1 and why the point mutation results in such drastic consequences. A better understanding of the mechanism of disease and the dysfunction of the mutant NFU1 at a fundamental level is essential in order to find a potential cure. An investigation into the structural and functional consequences of an additional cysteine residue at the binding pocket will serve to characterize the mutant protein and examine the cause of disease at a biochemical level.