Classification of the treble clef zinc finger: noteworthy lessons for structure and function evolution

Area of Science:

• Biochemistry
• Structural Biology
• Bioinformatics

Background:

• Treble clef (TC) zinc fingers are a large group of structural protein domains crucial for various cellular processes.
• Understanding their sequence, structure, and function relationships is key to deciphering their biological roles.

Purpose of the Study:

• To comprehensively analyze all TC domains in the Protein Data Bank.
• To identify novel TC structures and predict their functions.
• To investigate the evolutionary origins and functional diversity of TC domains.

Main Methods:

• Bioinformatic analysis of TC domain sequences and structures from the Protein Data Bank.
• Comparative analysis to identify structural variations and evolutionary relationships.
• Functional prediction based on structural and sequence homology.

Main Results:

• Identification of novel TC domains, including lsr2, YggX, and TFIIIC τ 60 kDa subunit.
• Prediction of nuclease-like function for the DUF1364 family.
• Observation of structural variations like circular permutation and resemblance to unrelated folds.
• Evidence that TC families do not share a single origin.
• Discovery of TC domains with functions beyond structure stabilization, including redox activity, nucleophilic acceptance, and catalysis.

Conclusions:

• TC zinc fingers exhibit significant structural plasticity and functional diversity.
• Their evolutionary history is complex, with multiple origins.
• Beyond structural roles, TC domains are involved in critical biochemical activities, expanding their known functional repertoire.