The structure and function of frataxin

Abstract

Frataxin, a highly conserved protein found in prokaryotes and eukaryotes, is required for efficient regulation of cellular iron homeostasis. Humans with a frataxin deficiency have the cardio- and neurodegenerative disorder Friedreich's ataxia, commonly resulting from a GAA trinucleotide repeat expansion in the frataxin gene. While frataxin's specific function remains a point of controversy, the general consensus is that the protein assists in controlling cellular iron homeostasis by directly binding iron. This review focuses on the structural and biochemical aspects of iron binding by the frataxin orthologs and outlines molecular attributes that may help explain the protein's role in different cellular pathways.

Figure 1

Top: ribbon diagram for yeast, human and bacterial frataxin. Middle: electropotential plots for proteins in same orientation. Bottom: electropotential plots for proteins rotated −90 degrees around the y-axis compared to top display. Structure figures made using solution structures of Yfh1 (PDB ID# 2GA5), HsFtx (PDB ID# 1LY7) and CyaY (PDB ID# 1SOY) frataxins.

Figure 2

ClustalX alignment for a subset of characterized frataxin orthologs. Bottom three sequences represent structurally characterized frataxin orthologs. Secondary structural elements and ruler representing Yfh1 properties are given below the sequences.

Figure 3

Yfh1 residues that are highly conserved on the helical (A) and β-sheet (B) planes of the protein. Identity of HsFtx FRDA point mutations on the helical (C) and β-sheet (D) planes of Yfh1. Structure figures made using Yfh1 solution structure (PDB ID# 2GA5).

Figure 4

Lowest energy simulation of Yfh1 monomer docked to the metal loaded yeast ferrochelatase. (A)Side view of single Yfh1 monomer (green) docked to yeast ferrochelatase dimer (dark and light blue). Co²⁺ is bound in the yeast ferrochelatase structure in the assembly active site close to the four membrane attachment lips at the bottom of the figure. (B) Side view (90°—Horizontal rotation of Figure 4A) showing monomeric Yfh1 interacts with both units in the ferrochelatase dimer. (C) Ferrochelatase side view with Yfh1 structure removed to show the residues that directly interact with frataxin (in red). (D) Electrostatic potential plots (calculated and vendered with Grasp) of ferrochelatase, side view. Figures A, B, and C prepared using VMD (Humphry et al., 1996). Docking simulations were performed using ZDock (Chen et al., 2003) using the Yfh1 structure simulations (PDB ID# 2GA5) and Co²⁺ loaded yeast ferrochelatase structure (PDB ID# 1L8X).