The human zinc-binding cysteine proteome.

Area of Science:

• Biochemistry
• Proteomics
• Molecular Biology

Background:

• Zinc is a vital micronutrient regulating physiological processes, primarily via binding to protein cysteine residues.
• The specific cysteine sites involved in zinc binding across the human proteome are largely uncharacterized.
• Understanding zinc-protein interactions is crucial for modulating protein function and cellular processes.

Purpose of the Study:

• To develop a comprehensive and quantitative map of the zinc-binding cysteine proteome (ZnCPT).
• To identify and characterize novel zinc-binding cysteine sites within human proteins.
• To explore the functional implications of zinc binding in various biological domains and disease contexts.

Main Methods:

• Development of ZnCPT, a deep and quantitative proteomic mapping technique.
• Systematic identification of cysteine residues involved in zinc binding across the human proteome.
• Analysis of protein families and functional domains regulated by zinc binding.

Main Results:

• Defined 6,173 zinc-binding cysteines, revealing widespread zinc modulation of protein function.
• Identified protein families across major biological domains affected by constitutive or inducible zinc binding.
• Discovered 52 cancer genetic dependencies influenced by zinc binding, including GSR-dependent lung cancers.

Conclusions:

• ZnCPT provides a valuable resource for understanding zinc regulation of protein function.
• Zinc binding plays a significant role in structural, enzymatic, and allosteric protein regulation.
• The findings nominate malignancies sensitive to zinc-induced cytotoxicity and reveal a novel zinc-GSR interaction in lung cancer.