Researchers from the University of Groningen have recently determined the three-dimensional structure of a membrane protein that explains how bacteria prepare a healthy vitamin cocktail. Their results were published last week in the online edition of the journal Nature Structural & Molecular Biology.
The structure is of the vitamin-binding subunit for vitamin B1 (thiamin), which is employed by a transport protein to take up thiamin. By exchanging this binding subunit for another, the transport protein can transport other vitamins depending on the specific requirements. Up to now it has been a mystery how the transport protein can exchange the different subunits so easily and how different subunits fit on the same transport protein.
Like humans, bacteria require vitamins for their growth. Many bacteria cannot produce these vitamins themselves and are therefore dependent on the uptake of vitamins from their environment. These vitamins are chemically very different and thus require very different vitamin -binding subunits. A three-dimensional structure is often an excellent way to understand a protein. Proteins are built up of a long chain of amino acids that is folded into a complex three-dimensional pattern. The exact structure of a protein mainly determines its function.
Transport proteins reside in the cell membrane and as a result of that, their properties are very different from proteins on the inside of the cell. These properties make membrane proteins notoriously difficult to study and determining their three-dimensional structure is particularly challenging. For instance, it is estimated that in total there are more than 20.000 protein structure available, whereas only 300 of these are membrane protein structures.
Proteins are generally too small to study with light microscopy. Therefore, the structure of proteins is often determined with X-ray crystallography. Large amounts of very pure protein are required to apply this technique. The purified protein is used to grow protein crystals, if these crystals are exposed to a high intensity X-ray beam from different directions, a diffraction pattern appears that reflects the shape of the protein in the crystal. The diffraction patterns are used to reconstruct the three-dimensional protein structure on a computer.
By comparing the structure of the vitamin-binding subunit for thiamin (named ThiT) with the previously published structure of a riboflavin (vitamin B2) binding subunit, the researchers found that although the proteins were different, their structures contained some striking similarities. By making small changes to the structure of ThiT, it was shown that for some changes the vitamin-binding subunit could no longer be recognized by the transport protein. By doing so, the researchers found out that the vitamin-binding subunit and the transport protein could fit together as ‘molecular Lego bricks’.
The vitamin transport research in Groningen was mainly driven by curiosity. Basic research is the starting point for applied research. A number of pathogenic bacteria are dependent on vitamin uptake for survival. With a good understanding of the mechanism of vitamin transport, it would be possible to start looking for molecules that block transport of vitamin-binding subunit exchange. These molecules could in the future be used for the development of new antibiotics.
Contact: Prof. Dirk Jan Slotboom
See also: online publication
The structural basis of modularity in ECF-type ABC transporters, Nature Structural & Molecular Biology, 26 juni 2011.Guus B. Erkens, Ronnie P-A. Berntsson, Faizah Fulyani, Maria Majsnerowska, Andreja Vujičić-Žagar, Josy ter Beek, Bert Poolman en Dirk Jan Slotboom
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