Comprehensive identification and functional analysis of fully disordered proteins essential for cell survival

Area of Science:

• Molecular Biology
• Genomics
• Biochemistry

Background:

• The classical protein structure-function paradigm posits that well-defined tertiary structures are essential for biological activity.
• This view implies that intrinsically disordered proteins (IDPs) may play lesser roles in cellular processes.
• Emerging evidence suggests that some IDPs are crucial for cellular functions, but their significance remains unclear.

Purpose of the Study:

• To investigate the essentiality of highly or fully disordered proteins using genome-wide screening.
• To challenge the traditional structure-function paradigm by assessing the role of protein disorder in cellular viability.
• To elucidate the biological significance of essential disordered proteins.

Main Methods:

• Genome-wide CRISPR screening was employed to assess gene essentiality across varying protein disorder levels.
• Comparative analysis of essentiality between well-folded and disordered proteins.
• Functional characterization of a specific essential fully disordered protein, FAM32A.

Main Results:

• Highly or fully disordered proteins demonstrate essentiality comparable to well-folded proteins.
• While structured proteins are more common among essential genes, the proportion of essential genes is similar across different disorder levels.
• Depletion of the essential disordered protein FAM32A resulted in increased intron retention and downregulation of other essential genes.

Conclusions:

• Disordered proteins, including fully disordered ones, are essential for cellular viability, reshaping the traditional structure-function paradigm.
• The study highlights the critical roles of proteins lacking defined tertiary structures in maintaining cellular functions.
• FAM32A serves as a key example of an essential disordered protein with significant regulatory functions.