Nature Structural Biology pp 461 - 465

Proteins are made of individual building blocks called amino acids, of which there are 20 different kinds. The amino acids are hooked together in long chains, and each protein gets its identity from the types of amino acids it contains and the order in which they are linked together—both of which are determined by the 'code' in a messenger RNA molecule that has been transcribed from a gene present in the DNA of an organism.

Messenger RNAs, and molecules called 'transfer RNAs' (tRNAs) because they help to transfer an amino acid to a growing protein chain, interact in a machine called the 'ribosome', where specific amino acids are linked together in the correct order. The messenger RNA contains sets of 'codons', which determine which amino acids will make up the protein. Each codon, which consists of 3 nucleotides, can only be paired with an 'anticodon' in a particular tRNA, and each of the 20 amino acids has a corresponding tRNA partner. This system ensures that there is only one way to translate the message into protein, and it must be very accurate for a cell to survive.

The reliability of translation depends in large part on enzymes called 'aminoacyl-tRNA synthetases', which are responsible for linking a specific amino acid to a particular tRNA. While much is known about how these enzymes recognize tRNAs it is less clear how they are able to tell the difference between amino acids that are similar in size and shape. Now, work by Dino Moras and coworkers at the CNRS in France shows how one such enzyme, threonyl-tRNA synthetase, achieves this challenging task.

In the case of threonyl-tRNA synthetase, previous studies suggested that a zinc ion participated in binding to the correct amino acid. Now, X-ray crystal structures of threonyl-tRNA synthetase bound to the amino acid threonine, provided by Moras and his colleagues, show that the zinc ion is directly involved in recognition of threonine. The zinc specifically interacts with two chemical groups on the threonine, making it the preferred amino acid substrate for this enzyme. This study reveals one way in which aminoacyl-tRNA synthetases manage to ensure the faithfulness of translation by recognizing only the correct amino acid.

Karin Musier-Forsyth and Penny Beuning, of the University of Minnesota, discuss these studies in an accompanying News and Views report.

Nature Structural Biology pp 514 - 520

The amino acid sequence of a protein specifies how it folds from a linear chain into its final structure. For discussion, a protein's structure can be categorized in three main ways: (i) as the linear array of amino acids, called the 'primary structure', that make up the protein, (ii) as the short stretches of alpha-helices and beta-strands, called 'secondary structures', that are defined by the kinds of amino acids that are present in the protein, and (iii) as the packing arrangement of the alpha-helices and beta-strands in the final folded state of the protein, which is called the 'tertiary structure'.

One key question in protein folding concerns the timing of formation of the secondary structures. Does folding proceed in a hierarchical manner—in other words, do the secondary structural elements appear first, and do they then simply dock together to form the tertiary structure? If the answer is yes, then one can tackle the protein folding problem, also in a hierarchical manner, by first characterizing the forces that drive the formation of the secondary structural elements, and then those that drive the docking reaction.

For many years, scientists have tried to answer this question. However, because secondary structures typically form within milliseconds after the start of the folding reaction, their efforts were hampered by not having an instrument that could accurately monitor structure formation in such a short time scale. To overcome this limitation, Morishima and coworkers at Kyoto University in Japan have developed an instrument that can monitor this rapid secondary structure formation.

The authors used this instrument to study folding of a small protein called cytochrome c that contains mostly alpha-helices, and they demonstrated that most of the helices are established within half a millisecond after the beginning of the folding process. At this time, the protein has not yet reached it final three-dimensional structure. Thus, these results suggest that folding of cytochrome c is indeed hierarchical (first secondary structures form, and then they dock together to form the tertiary structure) and that the rate-limiting step of the process is the search for tertiary structure docking contacts.

Syun-Ru Yeh and Denis Rousseau of Albert Eistein College of Medicine, USA, discuss these results in an associated News and Views.

Nature Structural Biology pp 505 - 513

Insects can be a serious problem for agriculture, and thus pest control is big business. Because of increasing resistance of insects to chemical pesticides, as well as growing awareness of the environmental damage caused by such pesticides, research is ongoing to find new insect control strategies.

Insects have many natural predators (such as spiders), and some of these produce protein toxins that can kill insects but not other kinds of animals. It has been suggested that using such toxins may be a more 'environmentally friendly' method of pest control.

However, in the venom of a predator, insect-specific toxins can sometimes be mixed in with other toxins that are capable of killing other kinds of animals. Separating the insect-specific toxins from the others is difficult, and thus there are few well-characterized insect-specific protein toxins.

Now, Glenn King, of the University of Connecticut in the USA, and coworkers have characterized a new family of insect-specific protein toxins from the funnel web spider Hadronyche versuta. They determined the three-dimensional structure of one of the members of this family by NMR spectroscopy, showing that the molecule has two distinct 'faces'—one is a very polar surface, and the other is devoid of charged residues. Thus, they name this family the 'janus- faced atracotoxins' (J-ACTXs), after Janus, the Roman god of gates and doorways who was often depicted with two faces looking in opposite directions.

Surprisingly, the non-polar face of the J-ACTX family member that they characterized contains a 'vicinal disulfide', which is a linkage between two adjacent cysteine amino acids. This kind of structure has not been seen in many other proteins, and King and coworkers show that it is important for the toxin's insect-killing activity.

Although the exact molecular target of the toxin could not be identified, the researchers were able to show that the likely site of action of this toxin family is the nervous system of insects.