A six-stranded double-psi beta barrel is shared by several protein superfamilies

Background: Six-stranded beta barrels with a pseudo-twofold axis are found in several proteins. One group comprises a Greek-key structure with all str ands antiparallel; an example is the N-terminal domain of ferredoxin reduct ase. Others involve parallel strands forming two psi structures (the double -gsi beta barrel). A recently discovered example of the latter class is asp artate-alpha-decarboxylase (ADC) from Escherichia coli, a pyruvoyl-dependen t tetrameric enzyme involved in the synthesis of pantothenate. Results: Visual inspection and automated database searches identified the s ix-stranded double-psi beta barrel in ADC, Rhodobacter sphaeroides dimethyl sulfoxide (DMSO) reductase, E. coli formate dehydrogenase H (FDHH), the pla nt defense protein barwin, Humicola insolens endoglucanase V (EGV) and, wit h a circular permutation, in the aspartic proteinases. Structure-based sequ ence alignments revealed several interactions including hydrophobic contact s or sidechain-mainchain hydrogen bonds that position the middle beta stran d under a psi loop, which may significantly contribute to stabilizing the f old. The identification of key interactions allowed the filtering of weak s equence similarities to some of these proteins, which had been detected by sequence database searches. This led to the prediction of the double-psi be ta-barrel domain in several families of proteins in eukaryotes and archaea. Conclusions: The structure comparison and clustering study of double-psi be ta barrels suggests that there could be a common homodimeric ancestor to AD C, FDHH and DMSO reductase, and also to barwin and EGV. There are other pro tein families with unknown structure that are likely to adopt the same fold . In the known structures, the protein active sites cluster around the psi loop, indicating that its rigidity, protrusion and free mainchain functiona l groups may be well suited to providing a framework for catalysis.