Fe-S clusters masquerading as zinc finger proteins.

Area of Science:

• Biochemistry and Molecular Biology
• Bioinorganic Chemistry
• Bioinformatics

Background:

• Metal ions are essential cofactors for over 25% of all proteins, playing crucial roles in structure and function.
• The evolution of Earth's oxygen-rich atmosphere altered metal bioavailability, influencing cofactor selection.
• Zinc finger proteins (ZF) are a major class of zinc-binding proteins, with 5% of the human genome annotated as ZFs.

Purpose of the Study:

• To highlight instances where proteins annotated as zinc finger proteins (ZF) are mis-annotated.
• To present specific examples of ZF proteins that instead harbor iron-sulfur (Fe-S) clusters.
• To describe methodologies for accurately differentiating between metal cofactors in these proteins.

Main Methods:

• Bioinformatic analysis for protein annotation.
• Review of empirical studies on specific protein examples.
• Description of experimental techniques for metal cofactor identification.

Main Results:

• Four specific examples of mis-annotated ZF proteins are identified: mitoNEET, CPSF30, nsp12, and Fep1.
• These proteins, predicted to bind zinc, were found to utilize iron-sulfur clusters.
• The study underscores the need for empirical validation beyond initial bioinformatic annotation.

Conclusions:

• Bioinformatic annotations of zinc finger proteins require empirical verification due to potential misclassification.
• Iron-sulfur clusters can be present in proteins annotated as zinc-binding, necessitating careful cofactor analysis.
• Accurate metal cofactor determination is critical for understanding protein function and biological pathways.