A Phosphorylation Switch Modulates Configurational Codes in the Oncofetal IGF2BP RNA Binding Paralogs

Area of Science:

• Molecular Biology
• Structural Biology
• RNA Biology

Background:

• Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1-3) are key regulators of mRNA fate.
• These proteins share structural similarity but exhibit paralog-specific functions.
• Their RNA-binding domains are linked by intrinsically disordered regions.

Purpose of the Study:

• To investigate the functional role of mTORC2-mediated phosphorylation on IGF2BP1 and IGF2BP3.
• To elucidate how phosphorylation impacts the structure and RNA-binding dynamics of IGF2BP paralogs.
• To understand the mechanism by which phosphorylation contributes to paralog-specific functions.

Main Methods:

• Site-specific phosphoserine incorporation.
• Structural and biophysical interrogations (e.g., X-ray crystallography, NMR, cryo-EM).
• RNA-binding assays and functional assays measuring mRNA translation and stability.

Main Results:

• Phosphorylation at a conserved serine residue acts as a configurational switch, reorganizing long-range domain arrangements.
• This rearrangement occurs in both RNA-free and RNA-bound states.
• Phosphorylation-induced structural changes are paralog-specific, leading to distinct configurational landscapes for IGF2BP1 and IGF2BP3, despite high sequence identity.

Conclusions:

• Phosphorylation is a critical post-translational modification that tunes IGF2BP paralog dynamics.
• Paralog-specific phosphorylation-dependent structural changes underlie differential mRNA recognition and functional outcomes.
• This mechanism provides insight into how IGF2BP paralogs program target mRNA selection and translational fate.