title: Structure of the arginine methyltransferase PRMT5-MEP50 reveals a mechanism for substrate specificity.
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.
authors: Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America. joeho@gate.sinica.edu.tw
authors: Meng-Chiao
authors: MC
authors: Ho
authors: Carola
authors: C
authors: Wilczek
authors: Jeffrey B
authors: JB
authors: Bonanno
authors: Li
authors: L
authors: Xing
authors: Janina
authors: J
authors: Seznec
authors: Tsutomu
authors: T
authors: Matsui
authors: Lester G
authors: LG
authors: Carter
authors: Takashi
authors: T
authors: Onikubo
authors: P Rajesh
authors: PR
authors: Kumar
authors: Man K
authors: MK
authors: Chan
authors: Michael
authors: M
authors: Brenowitz
authors: R Holland
authors: RH
authors: Cheng
authors: Ulf
authors: U
authors: Reimer
authors: Steven C
authors: SC
authors: Almo
authors: David
authors: D
authors: Shechter
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D008958:Models, Molecular; D011487:Protein Conformation; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D029867:Xenopus Proteins / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D029867:Xenopus Proteins; C570111:methylosome protein 50, Xenopus; C495466:Prmt5 protein, Xenopus; D011484:Protein-Arginine N-Methyltransferases