Building an iron-sulfur protein
Two proteins implicated in human disease play important roles in inserting clusters of iron and sulfur ions into proteins.
Proteins perform almost all of the tasks necessary for cells to survive. Some of these proteins need to contain collections of iron and sulfur ions known as iron-sulfur clusters to work properly. The iron-sulfur clusters are first assembled from individual ions and then attached to the correct target proteins. In humans, yeast and other eukaryotic cells, the first step of this process happens in compartments called mitochondria and makes a cluster that contains two of each ion, known as [2Fe-2S] clusters. These [2Fe-2S] clusters can either be directly incorporated into target proteins, or they may be used to make larger iron-sulfur clusters — such as [4Fe-4S] clusters — in the mitochondria or the main compartment of the cell (the cytoplasm).
Defects that affect the assembly of proteins with iron-sulfur clusters are associated with severe diseases that affect metabolism, the nervous system and the blood. Mitochondria contain at least 17 proteins involved in making iron-sulfur proteins, but there may be others that have not yet been identified. For example, a study on patients with a rare human genetic disease suggested that proteins called BOLA3 and NFU1 might also play a role in this process. Two groups of researchers investigated the roles these proteins play in the assembly of iron-sulfur clusters in yeast.
BOLA3 is closely related to the BOLA1 proteins. Marta Uzarska, Veronica Nasta, Benjamin Weiler and colleagues used biochemical techniques to show that the yeast equivalents of BOLA1 and BOLA3 (Bol1 and Bol3) play specific roles in the assembly pathway. When both of these proteins were missing from yeast, some iron-sulfur proteins — including an important enzyme called lipoic acid synthase — did not assemble properly. These experiments suggest that yeast Bol1 and Bol3 play overlapping and critical roles during the last step of iron-sulfur protein assembly when the iron-sulfur cluster is inserted into the target protein. Uzarska, Nasta, Weiler and colleagues also used biophysical techniques to show how Bol1 and Bol3 interact with Nfu1 and another mitochondrial protein involved in iron-sulfur protein assembly.
Andrew Melber and colleagues used genetics to study how [4Fe-4S] clusters are assembled in the mitochondria of yeast cells. The experiments show that Nfu1 and Bol3 act to incorporate completed [4Fe-4s] clusters into their target proteins. This process is particularly important when iron-sulfur clusters are in high demand, such as when a cell needs to produce a lot of energy. Melber and colleagues also showed that Bol1 is needed in an earlier stage of iron-sulfur cluster assembly.
Together these findings show that Bol1, Bol3 and Nfu1 play critical roles in iron-sulfur cluster assembly in yeast. Defects in assembling iron-sulfur proteins are generally more harmful to human cells than yeast cells. Therefore, the next step is to investigate what exact roles BOLA1, BOLA3 and NFU1 play in human cells and how similar this pathway is in different eukaryotes.
To find out more
Read the eLife research papers on which this eLife digest is based: “Mitochondrial Bol1 and Bol3 function as assembly factors for specific iron-sulfur proteins” and “Role of Nfu1 and Bol3 in iron-sulfur cluster transfer to mitochondrial clients” (August 17, 2016).
