Structural basis for MTA1c-mediated DNA N6-adenine methylation

Area of Science:

• Epigenetics and Molecular Biology
• Structural Biology
• Ciliate Genomics

Background:

• DNA N6-adenine methylation (6mA) is an emerging epigenetic mark in eukaryotes.
• The MTA1c complex in ciliates is a novel 6mA methyltransferase, but its mechanism is uncharacterized.

Purpose of the Study:

• To elucidate the structural mechanism of the MTA1c 6mA methyltransferase complex.
• To determine the roles of individual subunits (MTA1, MTA9, p1, p2) in catalysis and substrate binding.

Main Methods:

• X-ray crystallography was used to determine the structures of TthMTA1, PteMTA9-TthMTA1, TthMTA1-p1-p2, and TthMTA1-p2 complexes.
• Structures were solved in apo, S-adenosyl methionine (SAM)-bound, and S-adenosyl homocysteine (SAH)-bound states.
• Functional studies were conducted to assess subunit contributions to catalysis and cofactor binding.

Main Results:

• MTA1 is identified as the catalytically active subunit.
• Subunits p1 and p2 are crucial for forming the substrate DNA-binding channel.
• MTA9 stabilizes substrate binding, while MTA1 requires p2 assembly for stable SAM binding.

Conclusions:

• The study provides detailed structural and functional insights into the MTA1c complex.
• The findings clarify the mechanistic basis of 6mA methylation by this novel enzyme complex.
• This work enhances understanding of epigenetic regulation mediated by DNA methylation in ciliates.