Function and Structural highlights
General Aspects
Frataxin is a protein capable of storing, releasing and detoxifying intracellular iron. In humans, a mutation in this protein can trigger the Friedreich's ataxia, a neurodegenerative disease caused due to incapacity to form iron-sulfur groups necessary to activate the mitochondrial enzyme involved in the electron transportation chain, aconitase.
It consists of a polymeric molecule that, altought capable of forming larger complexes (as the 24 subunit oligomer detected by electron microscopy), exerts its activity by association of three subunits, enough to form a central channel where the ferroxidation takes place.
In the following paragraphs, we describe the general features of its structure in the trimeric form as obtaneid by X-ray cristalography at 3Å resolution. The protein used was obtained from the Y37A yeast, which has a 40% sequence identity to the human frataxin.
In the box at the right, it is possible to see its in a space-fill model, in which violet, orange and light-green represent, each, a different monomer from the entire molecule.
However, to cover some important aspects of the structure and function of the molecule, it is particularly useful to represent its .
General Secondary Structure Patterns
Stabilization of the Trimeric Tertiary Structure
The trimeric structure of frataxin is mainly stabilized by the of each subunit, shown in yellow. These consist of loops higly flexible in the monomer solution, but interestingly, when in the trimeric arragement, they play a crucial role in mantaining it. Viewing of the molecule, we can notice how the N-terminal extensions, still in yellow, interact with the adjacent monomer. Taking a , it is possible figure out how the N-terminal loop of the first monomer, here described as chain A, is placed with respect to chain B.
the details, it is possible to see some residues close enough to interact. The names associated with their positions can be seen by .
to rotate this region. We can the residues differently according to their hydrophilicity. In this new color scheme, polar residues are represented in pink while the hydrophobic ones appear gray. Now we are about to all those relevant residues to specify their interactions. The can be seen. Here, Pro 62, Val 65 and Leu 68, shown in dark-blue, are packed against the polar uncharged aminoacids Thr 110 and Thr 118, in red (other aminoacids are shown in turquoise). This interaction among the hydrophobic residues contributes to the maneintance of the loop configuration of the N-terminal region at its extremity. Another important interaction is the formed between Glu 64 and Thr 118. Those are the only residues able to form hydrogen bond, since the is within a range of approximately 3 Å (or 0.3 nm). , pay special attention it the role of the carbonyl oxygen of Glu 64 involved in the hydrogen bonding. In this color scheme, carbons are grey, oxygens are red and nitrogens are blue.
Now, we can devote our attention to examine what occurs at the .Those are the in relevant interactions that contribute to the stabilization of the trimeric form. Those are their specific (different colors of the labels simply indicates different subunits). to give emphasis on them, and to get a better spatial notion of its arrangement.
If we (recall: pink for charged aminoacids, and grey for aliphatic ones), it becomes evident their charged nature. Them, there is no hydrophobic packing taking place at this region. Instead, there are hydrogen bonds as the main eletrostatic interaction. Notice, again, the of each aminoacid: in this color scheme, again, we have C,O, and N.
There are six hydrogen-bonding pairs contributing to the stabilization of the molecule. Between , and , the pair is always formed between the carbonyls of the first and the amide groups of the second.
The other type of hydrogen bonding occurs between the side chains of the aminoacids involved in the pairs , and . In any of each ways, there is always an oxygen and a nitrogen involved.
The Role of the Channel
Disease
