Nature Structural Biology pp 380 - 383

Extremophiles—organisms that can grow and thrive under extreme physical conditions—have tremendous potential in biotechnology because of their ability to produce unique stable proteins with high technological value. In fact, a number of enzymes, such as ones involved in DNA processing, from several different extremophiles are already on the market.

A certain class of extremophiles are known as thermophiles because they grow best at temperatures of 50�C or higher. Proteins in thermophiles are very heat resistant—they maintain their proper three-dimensional structure even at very high temperatures, allowing the organism to endure the harsh environment.

What makes the proteins of a thermophile different from that of a mesophile (an organism that thrives at moderate temperature)? This question has been difficult to answer because the sequence of amino acids that make up mesophilic and thermophilic versions of the same protein typically differ at many positions even though they assume the same three-dimensional structure. Now, Franz Schmid and coworkers at the Universit�t Bayreuth in Germany have identified the key parts of a protein (certain amino acid residues) that render it resistant to heat.

By systematic mutagenesis, coupled with biochemical measurements, they found that the increased stability of the thermophilic version of a protein originates from only two amino acid residues present on the surface of the protein. They confirmed this conclusion by showing that they could stabilize the mesophilic protein by introducing just these two amino acids.

These results are very encouraging for the analysis of structure-function relationships and for understanding the molecular basis of protein thermostability. Such detailed information is critical if enzymes from extremophiles are to continue to be used in molecular biology and other industrial processes.

C. Nick Pace discusses these new results in an accompanying News & Views.

Nature Structural Biology pp 398 - 402

In the past decade, antibiotic-resistant bacteria such as strains of Escherichia coli, or bacteria that cause pneumonia or tuberculosis, have emerged as major health threats around the world. Preventing the spread of these microbes is an urgent task, and thus much research has recently been directed toward developing new antibiotics that could circumvent the antibiotic resistance problem.

To design good antibiotics with minimal side effects, researchers must first identify target processes that are essential to bacteria cells but not used by human cells. Then, drugs must be found to interfere with those target processes in the bacteria.

One such target process is the production of L-rhamnose, a sugar molecule that is found on the outside of many bacterial cells, incorporated into long chains of sugars, called polysaccharides. Polysaccharides containing L-rhamnose have been implicated in maintaining the strength of the bacterial cell wall, which surrounds the cell and protects it from environmental assaults. The polysaccharides containing L-rhamnose are also thought to be important for other processes, such as bacterial adhesion to various human tissues.

To understand how L-rhamnose is made, James H. Naismith and coworkers, at the University of St. Andrews in the UK, have determined the crystal structure of an enzyme, RmlC, that is important for the chemical synthesis of L-rhamnose inside bacterial cells.

This structure represents a starting point for the design of new drugs that could interfere with L-rhamnose synthesis, and thus potentially kill bacteria without harming human cells.

Nature Structural Biology pp 408 - 414

Not all cholesterol is bad for you. In fact, without some cholesterol, you couldn't live. One reason is that cholesterol is the starting point for making many important compounds, including steroid hormones that play essential roles throughout the body.

The steroidogenic acute regulatory protein (StAR) regulates the production of steroid hormones in kidneys and reproductive organs by promoting the transport of cholesterol into mitochondria, where the first step in steroid biosynthesis occurs.

Mutations in the StAR gene cause a disease called 'congenital lipoid adrenal hyperplasia'. Affected individuals cannot synthesize any steroid hormones. This results in many problems, including trouble retaining salt, a condition that can be life threatening because kidney failure can occur. In addition, since they cannot synthesize steroids, including those required for masculinization, affected individuals also have female genitalia, regardless of their chromosomal composition.

Now, Yosuke Tsujishita and James Hurley, of the National Institute of Diabetes and Digestive and Kidney Diseases in the USA have provided molecular insight into how the StAR protein functions, by solving the X-ray crystal structure of a protein domain that is highly related to the lipid transfer portion of StAR (a part of the protein called the START domain).

StAR-related lipid-transfer (START) domains occur in diverse proteins that are thought to be involved in lipid transport and metabolism, as well as other processes in the cell. Since START domain of the StAR protein was difficult to characterize in the test tube, the researchers determined the structure of highly related (by sequence comparisons) START domain of a protein called MLN64, hoping by analogy that they would obtain useful information about StAR.

The structure shows a 'tunnel' in the protein that, based on molecular modeling, appears to be perfectly suited for binding a single cholesterol molecule. This makes sense because the researchers show that the START domain of MLN64 binds cholesterol directly, in a 1:1 ratio. Interestingly, they also show that the START domain of StAR has this same property of binding cholesterol in a 1:1 ratio, and therefore, the structural information about MLN64 is probably relevant to understanding the mechanism of StAR function.

This structural and biochemical information is allowing scientists to analyze the different proposals for the function of the StAR protein. For example, these new data support a simple model—that StAR shuttles cholesterol into mitochondria. If StAR is inactive, as in the case of the disease mutations, no cholesterol gets into the mitochondria, and hence no steroid biosynthesis can occur.