A common fold

Telomeric DNA terminates in a single-stranded overhang, and several proteins bind these overhangs to protect them from degradation and fusion. Such proteins include the Oxytricha nova telomere-end-binding protein (TEBP), Schizosaccharomyces pombe protection of telomeres 1 (Pot1), human Pot1 and Saccharomyces cerevisiae Cdc13. The Pot proteins were identified on the basis of weak sequence similarity to TEBP, but no similarity between any of these proteins and Cdc13 has been found. Now, however, Wuttke and colleagues report in Science that Cdc13 and TEBP use a common fold for telomeric-DNA interactions.

The authors determined the solution structure of the Cdc13 DNA-binding domain bound to telomeric single-stranded DNA, and found that Cdc13 is a member of the oligonucleotide-binding superfamily of OB-fold proteins. The OB motif ? a β barrel composed of two, three-stranded antiparallel β sheets packed orthogonally ? is used to bind oligonucleotides, oligosaccharides and oligopeptides, and, at present, it cannot be predicted using sequence comparisons. So, despite the lack of sequence similarity, Wuttke and co-workers showed that the Cdc13 OB fold is highly similar to that of O. nova TEBP, and conclude that structure-based comparisons should be used to assess homology in divergent proteins. They also conclude that the structural and functional similarities between Cdc13 and the other telomere-end-binding proteins indicate the evolutionary conservation of telomeric-end-protection mechanisms. REFERENCE Mitton-Fry, R. M. et al. Conserved structure for single-stranded telomeric DNA recognition. Science 296, 145?147 (2002)

A new folding machine

Molecular chaperones and proteases monitor protein folding, and distinguish misfolded proteins that can be correctly refolded from those that should be degraded. Unique insights into one such protease?chaperone machine ? DegP (HtrA) from Escherichia coli ? have now come from Clausen and co-workers, who describe its crystal structure in Nature.

The authors found that each DegP monomer has three domains ? a protease domain and two PDZ domains. The functional DegP hexamer is formed by the staggered association of two rings, each comprising three DegP monomers. The protease domains form the 'top' and 'bottom' of the structure, and the PDZ domains make up the side walls. Clausen and colleagues observed two states for the hexamer. One state is 'open', with a wide lateral cavity through the oligomer, whereas the other state is 'closed' ? a change that is mediated by the mobile PDZ domains.

Clausen and co-workers found that the proteolytic sites are situated in the cavity, which is only accessible laterally. They propose that the PDZ domains are involved in initial substrate interactions, and that hydrophobic patches in the cavity might subsequently bind unfolded proteins. The structure of the DegP hexamer is different from other cage-forming proteins, in which substrates enter a central cavity through narrow axial or lateral pores, so these authors have provided the structural basis to further understand the mechanism of this new type of protease?chaperone machine. REFERENCE Krojer, T. et al. Crystal structure of DegP (HtrA) reveals a new protease?chaperone machine. Nature 416, 455?459 (2002)