A tale of two ferredoxins: sequence similarity and structural differences.
BACKGROUND
Sequence similarity between proteins is usually considered a reliable indicator of homology. Pyruvate-ferredoxin oxidoreductase and quinol-fumarate reductase contain ferredoxin domains that bind [Fe-S] clusters and are involved in electron transport. Profile-based methods for sequence comparison, such as PSI-BLAST and HMMer, suggest statistically significant similarity between these domains.


RESULTS
The sequence similarity between these ferredoxin domains resides in the area of the [Fe-S] cluster-binding sites. Although overall folds of these ferredoxins bear no obvious similarity, the regions of sequence similarity display a remarkable local structural similarity. These short regions with pronounced sequence motifs are incorporated in completely different structural environments. In pyruvate-ferredoxin oxidoreductase (bacterial ferredoxin), the hydrophobic core of the domain is completed by two beta-hairpins, whereas in quinol-fumarate reductase (alpha-helical ferredoxin), the cluster-binding motifs are part of a larger all-alpha-helical globin-like fold core.


CONCLUSIONS
Functionally meaningful sequence similarity may sometimes be reflected only in local structural similarity, but not in global fold similarity. If detected and used naively, such similarities may lead to incorrect fold predictions.
Krishna
S Sri
SS
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA. krishna@sdsc.edu
Sadreyev
Ruslan I
RI
Grishin
Nick V
NV
D000595:Amino Acid Sequence; D019295:Computational Biology; D003901:Desulfovibrio / Q000737:chemistry; D004926:Escherichia coli / Q000737:chemistry; D019143:Evolution, Molecular; D005288:Ferredoxins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D012984:Software
D005288:Ferredoxins