Structural basis for the recognition of transiently structured AU-rich elements by Roquin

Area of Science:

• Molecular Biology
• RNA Biology
• Structural Biology

Background:

• Adenylate/uridylate-rich elements (AREs) are common mRNA regulatory sequences in the 3'-UTR.
• AREs bind RNA-binding proteins (RBPs) to mediate mRNA decay and regulate gene expression.
• The immunoregulatory RBP Roquin was proposed to recognize folded AREs as constitutive decay elements (CDEs).

Purpose of the Study:

• To provide structural evidence for CDE-like recognition of AREs by Roquin.
• To investigate the structural basis of ARE recognition by different RBPs.
• To understand how ARE conformational states influence RBP binding and mRNA regulation.

Main Methods:

• X-ray crystallography to determine the structures of AREs in free and protein-bound forms.
• Structural analysis of ARE-RBP complexes.
• Biochemical assays to assess RBP binding to different ARE conformations.

Main Results:

• Structures of CDE-like folded AREs bound to Roquin were determined.
• The UCP3 3'-UTR ARE was found to be bound by AUF1 in a linear form, distinct from Roquin's CDE recognition.
• AREs exhibit distinct conformational states enabling differential recognition by regulatory RBPs.

Conclusions:

• AREs can be recognized by RBPs in multiple ways depending on their conformational state.
• Distinct ARE structures provide differential accessibility to regulatory RBPs, allowing fine-tuned mRNA regulation.
• This multi-faceted recognition mechanism enhances the plasticity and efficacy of mRNA regulation.