Structural basis for the dual RNA-recognition modes of human Tra2-β RRM

Area of Science:

• Molecular Biology
• Structural Biology
• Genetics

Background:

• Human Transformer2-β (hTra2-β) is a key serine/arginine-rich protein.
• It regulates alternative splicing of critical pre-mRNAs like CGRP, SMN1, and tau.
• The hTra2-β protein contains a single RNA recognition motif (RRM).

Purpose of the Study:

• To determine the structural basis of RNA recognition by the hTra2-β RRM.
• To elucidate the distinct binding modes for different RNA sequences.

Main Methods:

• Solution structure determination of the hTra2-β RRM.
• Co-complex structure determination of the hTra2-β RRM with the (GAA)2 RNA sequence.
• Nuclear Magnetic Resonance (NMR) experiments.

Main Results:

• The hTra2-β RRM possesses a canonical fold with an unusual aromatic amino acid arrangement on its β-sheet surface.
• Specific recognition of the AGAA sequence within (GAA)2 involves hydrogen bonds and aromatic stacking interactions.
• The CAA sequence is recognized when integrated into a stem-loop structure.

Conclusions:

• The hTra2-β RRM employs different RNA binding strategies for distinct RNA sequences.
• These findings provide insights into the molecular mechanisms of alternative splicing regulation by hTra2-β.