Structural Insights into Ternary Complex Formation of Human CARM1 with Various Substrates

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Coactivator-associated arginine methyltransferase 1 (CARM1) is a key enzyme in cancer, known to methylate histone H3 and other proteins.
• Previous studies solved CARM1 structures with inhibitors, but lacked ternary structures detailing substrate interactions.

Purpose of the Study:

• To elucidate the structural basis of CARM1's substrate recognition and binding.
• To present the first ternary structures of CARM1 with both a cofactor mimic and diverse peptide substrates.

Main Methods:

• X-ray crystallography was employed to determine the structures of human CARM1.
• Structures were solved in complex with sinefungin (an S-adenosylmethionine mimic) and three distinct peptide sequences (from histone H3 and PABP1).

Main Results:

• The study presents crystal structures of human CARM1 bound to sinefungin and peptides, showcasing both unmethylated and monomethylated arginine residues.
• This work is the first to solve multiple substrate sequences within a single protein arginine methyltransferase (PRMT) enzyme.
• The CARM1 binding site demonstrates adaptability to various peptide sequences while maintaining a conserved binding mode for substrates.

Conclusions:

• The presented structures provide a detailed understanding of how CARM1 accommodates different peptide substrates.
• Comparative analysis with other PRMT structures reveals potential conserved hydrogen bonding patterns in substrate binding sites.
• These findings contribute to understanding CARM1's role in biological processes and cancer, potentially guiding future drug design.