Please quote Nature Structural & Molecular Biology as the source of these items.

The January 2004 issue of Nature Structural & Molecular Biology is available online.

Nature Structural & Molecular Biology pp 45 - 53

A single gene can code for a set of related protein isoforms, each with different tissue specificity and slightly altered functional capability tailored to the needs of a cell. A paper in the January issue of Nature Structural & Molecular Biology shows that an isoform of the neuronal protein Piccolo has an altered structure that can no longer respond to cellular signals. The findings suggest how Piccolo can mediate communicate between brain cells.

Piccolo is one of the proteins that organize the active zone of a synapse, the region where vesicles at the end of one neuron await a signal to release their cargos, the neurotransmitters. Piccolo responds to calcium and affects vesicle fusion and subsequent neurotransmitter release at the synapse. Rizo and colleagues at the University of Texas Southwestern Medical Center show that an isoform of Piccolo containing an additional nine amino acids in the calcium-binding domain causes a rearrangement of the protein structure. This rearrangement results in a decreased ability of Piccolo to bind calcium ions and phospholipids, two functions necessary for transmitting signals between neurons. The brain contains many isoforms of Piccolo, so cells harboring different Piccolo isoforms may respond to calcium in different ways or not at all, resulting in a specific communication pathway between neurons.

Nature Structural & Molecular Biology pp 73 - 80

Hemoglobin synthesis is a key step in the final stage of red blood cell maturation, but until recently the molecular events leading to its production had not been clearly defined. In the January issue of Nature Structural & Molecular Biology, a paper reports the changes in the protein complexes regulating the transcription of the hemoglobin genes during red blood cell differentiation. This study provides a system-wide view of the cell in response to a differentiation signal.

Using a quantitative proteomic approach, Mark Groudine and colleagues at the Fred Hutchinson Cancer Research Center, as well as collaborators at the Institute for Systems Biology and at Stanford University, characterize the components in the transcription factor complexes associated with the globin gene locus in red blood cells, both before and after terminal differentiation. They find that a key transcription factor called MafK interacts with a different protein partner before and after differentiation. Associated with this exchange of partners is the presence of co-repressor and co-activator molecules at the globin gene locus, as well as the recruitment of many other protein molecules that have not been previously implicated in the regulation of transcription. The results thus reveal the complexity and the dynamic nature of interactions between proteins in controlling hemoglobin synthesis during the maturation process of red blood cells.

Nature Structural & Molecular Biology pp 29 - 35

The synthesis of some proteins inside the cell is regulated in response to metabolite small molecules. In a paper in the January issue of Nature Structural & Molecular Biology, Maumita Mandal and Ronald Breaker offer insight into how one sensing molecule is able to discriminate between two closely related metabolite molecules.

Certain RNA molecules, termed riboswitches, can act as sensor molecules and, together with other proteins, act to control gene expression. A previous study described a riboswitch that controls gene expression in response to binding the purine base guanine. In this study, Mandal and Breaker show that riboswitches that respond to the closely related purine base adenine also exist within the cell. They demonstrate that a single change in the RNA can alter the binding preference of guanine- and adenine-sensing riboswitches between guanine and adenine.

The adenine riboswitch functions as a genetic on-switch, whereby adenine binding to the riboswitch produces a structural change that disrupts a transcription terminator, allowing for increased levels of gene expression. This is notable because in the majority of riboswitches examined so far, metabolite binding leads to decreased expression levels. Thus, the newly identified adenine-sensing riboswitch expands the functionality of known riboswitches.

Nature Structural & Molecular Biology pp 60 - 66 and 67 - 72

Development of treatment for anthrax is an urgent task, especially given the threat of its use in bioterrorism. Two papers in the January issue of Nature Structural & Molecular Biology now report the development of approaches to directly target an anthrax toxin to stop its lethal activity. These approaches complement the development of antibiotics that could prevent the spread of the bacteria.

Anthrax lethal factor, one of three toxins secreted by the deadly microorganism, causes cell death by inactivating key signaling molecules. Using parallel screening approaches, groups led by Lewis Cantley (Harvard Medical School) and Sina Bavari (US Army Medical Research Institute of Infectious Diseases) identified peptide analogs and small molecules, respectively, that inhibit the activity of lethal factor. Notably, some of these compounds can protect cells against the lethal activity of the toxin. Structure analyses of lethal factors in complex with the inhibitors explain how these compounds interact with the toxin and suggest how they could be improved. These compounds are templates for the development of more effective treatments directed toward lethal factor.