4G56

Crystal Structure of full length PRMT5/MEP50 complexes from Xenopus laevis

Summary for 4G56

• Entry DOI: 10.2210/pdb4g56/pdb
• Descriptor: Hsl7 protein, MGC81050 protein, S-ADENOSYL-L-HOMOCYSTEINE, ... (4 entities in total)
• Functional Keywords: protein arginine methyltransferase, protein complexes, histone methylation, transferase, structural genomics, psi-biology, new york structural genomics research consortium, nysgrc
• Biological source: Xenopus laevis (clawed frog,common platanna,platanna); More
• Cellular location: Cytoplasm: Q6NUA1 Q6NUD0
• Total number of polymer chains: 4
• Total formula weight: 229941.22

Authors

Ho, M.,Wilczek, C.,Bonanno, J.,Shechter, D.,Almo, S.C.,New York Structural Genomics Research Consortium (NYSGRC) (deposition date: 2012-07-17, release date: 2012-10-03, Last modification date: 2024-10-30)

Primary citation

Ho, M.C.,Wilczek, C.,Bonanno, J.B.,Xing, L.,Seznec, J.,Matsui, T.,Carter, L.G.,Onikubo, T.,Kumar, P.R.,Chan, M.K.,Brenowitz, M.,Cheng, R.H.,Reimer, U.,Almo, S.C.,Shechter, D.
Structure of the arginine methyltransferase PRMT5-MEP50 reveals a mechanism for substrate specificity
Plos One, 8:e57008-e57008, 2013

PubMed 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.

PubMed: 23451136
DOI: 10.1371/journal.pone.0057008

Experimental method

X-RAY DIFFRACTION (2.95 Å)