Structure of the Arginine Methyltransferase PRMT5-MEP50 Reveals a Mechanism for Substrate Specificity
Year: 2013
Type: article
Abstract: The arginine methyltransferase PRMT5-MEP50 is required for embryogenesis and is misregulated in many cancers. PRMT5 targets a wide variety of substrates, including histone proteins involved in specifying an epigenetic code. However, the mechanism by which PRMT5 utilizes MEP50 to discriminate substrates and to specifically methylate target arginines is unclear. To test a model in which MEP50 is critical for substrate recognition and orientation, we determined the crystal structure of Xenopus laevis PRMT5-MEP50 complexed with S-adenosylhomocysteine (SAH). PRMT5-MEP50 forms an unusual tetramer of heterodimers with substantial surface negative charge. MEP50 is required for PRMT5-catalyzed histone H2A and H4 methyltransferase activity and binds substrates independently. The PRMT5 catalytic site is oriented towards the cross-dimer paired MEP50. Histone peptide arrays and solution assays demonstrate that PRMT5-MEP50 activity is inhibited by substrate phosphorylation and enhanced by substrate acetylation. Electron microscopy and reconstruction showed substrate centered on MEP50. These data support a mechanism in which MEP50 binds substrate and stimulates PRMT5 activity modulated by substrate post-translational modifications.
Source: PLoS ONE
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: U.S. Department of Energy, Albert Einstein Cancer Center, National Science Council, Academia Sinica, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Biomedical Imaging and Bioengineering, National Center for Research Resources, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory
Awards: G1026088249, G113944070, G2463063366, G2638674773, The NYSGRC: A Large Scale Center for PSI:Biology, Macromolecular Crystallography at the National Synchrotron Light Source, G4262416891, G492198676, G5368254702, G5745650740, G597898291, G6915411751, Macromolecular Crystallography at the National Synchrotron Light Source, Present Homologous and Heterologous Antigen with Hepatitis E Virus, G7982793873, G9000028044, G9000035606, G9000042503, G9000108980, G9000240216, Cancer Center Support Grant
OpenAlex ID: W2072731237