Human DND1-RRM2 forms a non-canonical domain swapped dimer.

Area of Science:

• Structural Biology
• Molecular Biology
• Biochemistry

Background:

• RNA recognition motifs (RRMs) are abundant RNA-binding domains crucial for eukaryotic cellular regulation.
• While canonical RRM structures are known, variations in their topology exist.
• The DND1 protein's RRM2 domain is implicated in cellular processes, but its structural characteristics are not fully understood.

Purpose of the Study:

• To determine the crystal structure of the human DND1-RRM2 domain.
• To elucidate the structural basis for any observed non-canonical fold.
• To investigate the molecular mechanisms underlying domain-swapped dimerization in RRMs.

Main Methods:

• X-ray crystallography to determine the 2.3 Å resolution structure of human DND1-RRM2.
• Nuclear Magnetic Resonance (NMR) spectroscopy to explore protein dynamics at the residue level.
• Molecular Dynamics (MD) simulations to complement experimental dynamics data.

Main Results:

• The human DND1-RRM2 domain adopts a non-canonical RRM fold.
• A stable 3D domain-swapped dimer is formed through interactions between β1 and β4 strands across protomers.
• NMR and MD simulations identified key residues and dynamics responsible for the stable domain-swapped dimer formation.

Conclusions:

• The study reveals a novel, non-canonical RRM fold in human DND1-RRM2, characterized by 3D domain-swapped dimerization.
• The findings provide a detailed molecular understanding of the determinants and mechanisms driving this unique dimerization.
• This work expands the known structural diversity of RRM domains and their regulatory potential.