Nature Structural Biology pp 27 - 31

Spinal muscular atrophy (SMA) is an inherited disease that is one of the most common causes of death in infancy. It occurs in ~1 in 6,000 live births, second only to cystic fibrosis. Milder forms of SMA are also found in older children and adults.

In SMA, the certain cells in the spinal cord die, resulting in progressive muscle weakness and ultimately, in some cases, in the inability to breathe and swallow.

The gene that is mutated in SMA has been identified, but we still have little understanding of how the encoded protein functions to allow survival of the motor neurons. This protein is called the 'survival of motor neuron' (SMN) protein, and it has been implicated in the basic cellular process of RNA metabolism.

Now, Michael Sattler, of the European Molecular Biology Laboratory in Heidelberg, Germany, and colleagues present the three-dimensional structure of one part of the SMN protein, determined using the technique of NMR spectroscopy. They also present the results of experiments with an SMN protein that harbors a mutation found in SMA patients. This mutation prevents SMN from interacting with key partner proteins, called Sm proteins. Sattler and colleagues show that this mutation has a very specific, local effect at the site of the mutation (instead of a global, deleterious structural effect on the protein).

The Sm proteins are fundamental components of the machinery in cells that performs the task of RNA splicing, one of the final steps in gene expression. The results of Sattler and colleagues are a step toward understanding how the loss of the interaction between SMN and the Sm proteins could lead to death of motor neurons in SMA patients.

The News and Views by Alex MacKenzie and Nathalie Gendron places this work into the context of the cellular machinery, and the Editorial discusses SMA more broadly.

Nature Structural Biology pp 23 - 26

If you are a healthy individual, perhaps you do not worry much about infection by a bacterium called Pseudomonas aeruginosa. However, if you suffer from cystic fibrosis or severe burns, infection by this microbe could be lethal. Give it a chance and this opportunistic pathogen would infect almost all tissues in a human body, including the respiratory system, heart valves and urinary tract. Unfortunately, P. aeruginosa is resistant to many antibiotics, making treatment difficult. Development of new drugs against this pesky bug is therefore an urgent task.

Pseudomonas aeruginosa produces a variety of toxins, one of which is exotoxin S (ExoS). Because disruption of the gene encoding ExoS significantly reduces the virulence of the bacteria, ExoS plays an important role in the pathogenicity of P. aeruginosa. One function of ExoS is to activate the GTPase activity of small G proteins in the host cells that are involved in rearranging cytoskeleton; this activity may allow P. aeruginosa to escape the defense mounted by the host.

To define the mechanism of how ExoS regulates G protein activity, Alfred Wittinghofer and coworkers of Max-Planck-Institut fur Molekulare Physiologie, Germany, have determined the crystal structure of the N-terminal domain of ExoS (ExoS-N) in complex with a human G protein, Rac. The results reveal that both the structure of ExoS-N and its interactions with Rac are different from those of other GTPase-activating proteins for Rac in the host cell. These differences may provide the basis for new drugs that could attenuate the virulence of P.aeruginosa. The structure thus represents an early step toward curbing P. aeruginosa infection.

Nature Structural Biology pp 37 - 41

If you are a healthy individual, perhaps you do not worry much about infection by a bacterium called Pseudomonas aeruginosa. However, if you suffer from cystic fibrosis or severe burns, infection by this microbe could be lethal. Give it a chance and this opportunistic pathogen would infect almost all tissues in a human body, including the respiratory system, heart valves and urinary tract. Unfortunately, P. aeruginosa is resistant to many antibiotics, making treatment difficult. Development of new drugs against this pesky bug is therefore an urgent task.

Pseudomonas aeruginosa produces a variety of toxins, one of which is exotoxin S (ExoS). Because disruption of the gene encoding ExoS significantly reduces the virulence of the bacteria, ExoS plays an important role in the pathogenicity of P. aeruginosa. One function of ExoS is to activate the GTPase activity of small G proteins in the host cells that are involved in rearranging cytoskeleton; this activity may allow P. aeruginosa to escape the defense mounted by the host.

To define the mechanism of how ExoS regulates G protein activity, Alfred Wittinghofer and coworkers of Max-Planck-Institut fur Molekulare Physiologie, Germany, have determined the crystal structure of the N-terminal domain of ExoS (ExoS-N) in complex with a human G protein, Rac. The results reveal that both the structure of ExoS-N and its interactions with Rac are different from those of other GTPase-activating proteins for Rac in the host cell. These differences may provide the basis for new drugs that could attenuate the virulence of P.aeruginosa. The structure thus represents an early step toward curbing P. aeruginosa infection.