Conformational buffering underlies functional selection in intrinsically disordered protein regions.

Area of Science:

• Molecular biology
• Biochemistry
• Genetics

Background:

• Disordered proteins often maintain function despite sequence variation.
• Identifying mechanisms of functional selection in these proteins is challenging.
• Adenovirus early gene 1A (E1A) protein is a key regulator of cell cycle.

Purpose of the Study:

• To elucidate the molecular mechanism of functional selection for the disordered E1A protein.
• To understand how E1A achieves high-affinity binding to the retinoblastoma (Rb) protein.
• To investigate the role of disordered linkers in protein function and evolution.

Main Methods:

• Analysis of E1A protein structure-function relationships.
• Investigating binding interactions between E1A, Rb protein, and host factors.
• Studying sequence variation and coevolution in E1A protein families.

Main Results:

• E1A utilizes two binding motifs tethered by a disordered linker for picomolar affinity Rb binding.
• Compensatory sequence changes in motifs and linkers maintain optimal tethering (conformational buffering).
• Coevolution of motifs and linker preserves or alters the E1A tethering mechanism.

Conclusions:

• Conformational buffering and motif-linker coevolution explain functional robustness in disordered E1A linkers.
• These mechanisms contribute to functional selection in hypervariable disordered protein regions.
• The findings provide insights into the evolution and adaptation of disordered proteins.