Featured System - February 2009
Short description: Research in bioinformatics has shown that proteins are often modular, and that these modules are often mixed and matched to form new proteins.
Research in bioinformatics has shown that proteins are often modular, and that these modules are often mixed and matched to form new proteins. Researchers at the PSI MCSG have recently determined the structure of a protein with a new combination of two familiar modules, and made the first steps towards uncovering the function of this unusual new family of proteins.
The first clue that this family of proteins might be something interesting came from an analysis of amino acid sequences. In a search of proteins that contain a typical sequence for CBS domains, MCSG researchers found several that were connected to a short unannotated sequence with four cysteine amino acids. CBS domains are found in a variety of proteins, such as cystathionine beta-synthase (CBS), where they often act as modules for the binding of ATP and other adenosine small molecules. In this role, the CBS module can add a regulatory function to a protein, changing the activity of the protein based on the levels of ATP in the cell. CBS modules also play structural roles, by forming protein-protein interaction sites in oligomeric complexes. But what was this short cysteine-rich extension doing?
Based on the sequence, the cysteine-rich extension in this new family of proteins was predicted to be similar to Zn ribbon domains. These are a subset of the large superfamily of zinc fingers, which play diverse roles in recognition of DNA, proteins, and small molecules. The four cysteine amino acids in these proteins are arranged to form a tetrahedral cage that traps zinc and other metal ions. The zinc ions typically play a structural role, folding the short protein chain into a stable, globular structure. In some cases, however, the metal ion plays other functional roles.
When TA0289 was purified, it showed a compelling reddish-purple color, which may give a hint to its function. The color is caused by the binding of iron ions in the metal-binding site. This is similar to the small redox protein rubredoxin, which contains a similar iron-binding site and shows a similar beautiful color when purified. With testing, MCSG researchers found that TA0289 can transport electrons, suggesting that it may perform this function inside cells. The CBS domain links the two chains into a stable dimer, so its role may be primarily structural. Although the reason that TA0289 needs to be a dimer is still a mystery...the two iron binding sites are too far apart to transfer electrons to one another. You can take a look at this protein structure in the PDB entry 2qh1.
The JSmol tab below displays an interactive JSmol.
Ribonuclease inhibitor is a horseshoe-shaped protein that is composed of a series of repeated helix-sheet modules. Ribonuclease (shown in red) binds inside the horseshoe. Use the buttons below to look at the two steering arginine amino acids and their interaction with aspartates on the inhibitor.
M. Proudfoot, S. A. Sanders, A. Singer, R. Zhang, G. Brown, A. Binkowski, L. Xu, J. A. Lukin, A. G. Murzin, A. Joachimiak, C. H. Arrowsmith, A. M. Edwards, A. V. Savchencko, and A. F. Yakunin. (2008) Biochemical and structural characterization of a novel family of cystathionine beta-synthase domain proteins fused to a Zn ribbon-like domain. J. Mol. Biol. 375, 301-315.