Protein Arginine Methyltransferase 8: Tetrameric Structure and Protein Substrate Specificity

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Type I protein arginine methyltransferases (PRMTs) are crucial enzymes involved in protein post-translational modifications.
• Dysregulation of PRMTs is linked to cancer and developmental disorders.
• The substrate recognition mechanism of PRMTs at the protein level remains largely unknown.

Purpose of the Study:

• To elucidate the structural basis of PRMT8 function and substrate recognition.
• To identify novel substrates and regulatory mechanisms of PRMT8.
• To provide insights into potential therapeutic strategies targeting PRMTs.

Main Methods:

• X-ray crystallography to determine the structure of PRMT8:SAH complex.
• Small-angle X-ray scattering (SAX) to analyze PRMT8 quaternary structure in solution.
• Site-directed mutagenesis to investigate the role of specific regions in substrate recognition and methylation activity.

Main Results:

• The crystal structure of PRMT8:SAH complex revealed a unique dimer of dimers (tetrameric) architecture, distinct from other type I PRMTs.
• A novel non-histone substrate, NIFK, was identified for PRMT8.
• A specific regulatory region (PRMT8-β15) was found essential for NIFK recognition, while not affecting histone or peptide methylation.
• Two distinct conformations (open and closed) of PRMT8 were observed, correlating with SAH binding.

Conclusions:

• PRMT8 exhibits a unique tetrameric structure and substrate recognition mechanism involving a specific regulatory region.
• The findings provide a structural basis for PRMT8's substrate specificity and offer potential avenues for developing PRMT1/8 inhibitors.