A tale of two ferredoxins: sequence similarity and structural differences.

Area of Science:

• Biochemistry
• Structural Biology
• Bioinformatics

Background:

• Ferredoxin domains in pyruvate-ferredoxin oxidoreductase and quinol-fumarate reductase bind [Fe-S] clusters and are vital for electron transport.
• Profile-based methods like PSI-BLAST and HMMer detect significant sequence similarity between these ferredoxin domains.

Purpose of the Study:

• To investigate the nature of sequence similarity between ferredoxin domains from different protein families.
• To determine if sequence similarity correlates with structural similarity in these domains.

Main Methods:

• Sequence comparison using profile-based methods (PSI-BLAST, HMMer).
• Structural analysis of ferredoxin domains from pyruvate-ferredoxin oxidoreductase and quinol-fumarate reductase.
• Detailed examination of [Fe-S] cluster-binding sites and surrounding structural elements.

Main Results:

• Sequence similarity is concentrated in the [Fe-S] cluster-binding regions.
• While overall protein folds differ, these specific regions exhibit remarkable local structural similarity.
• These conserved motifs are integrated into distinct structural contexts: beta-hairpins in bacterial ferredoxin and an alpha-helical core in alpha-helical ferredoxin.

Conclusions:

• Functionally relevant sequence similarity can manifest as local structural similarity, independent of global fold conservation.
• Naïve interpretation of sequence similarity without considering structural context may lead to inaccurate protein fold predictions.