5dx1
From Proteopedia
Crystal structure of CARM1, sinefungin, and PABP1 peptide (R455)
Structural highlights
Function[CARM1_HUMAN] Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs.[1] [2] [PABP1_HUMAN] Binds the poly(A) tail of mRNA. May be involved in cytoplasmic regulatory processes of mRNA metabolism such as pre-mRNA splicing. Its function in translational initiation regulation can either be enhanced by PAIP1 or repressed by PAIP2. Can probably bind to cytoplasmic RNA sequences other than poly(A) in vivo. Involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. Involved in regulation of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons; for the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed.[3] [4] Publication Abstract from PubMedCoactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine N-methyltransferase (PRMT) enzyme that has been implicated in a variety of cancers. CARM1 is known to methylate histone H3 and nonhistone substrates. To date, several crystal structures of CARM1 have been solved, including structures with small molecule inhibitors, but no ternary structures with nucleoside and peptide substrates have been reported. Here, the crystal structures of human CARM1 with the S-adenosylmethione (SAM) mimic sinefungin and three different peptide sequences from histone H3 and PABP1 are presented, with both nonmethylated and singly methylated arginine residues exemplified. This is the first example of multiple substrate sequences solved in a single PRMT enzyme and demonstrates how the CARM1 binding site is capable of accommodating a variety of peptide sequences while maintaining a core binding mode for the unmethylated and monomethylated substrates. Comparison of these with other PRMT enzyme-peptide structures shows hydrogen bonding patterns that may be thematic of these binding sites. Structural Insights into Ternary Complex Formation of Human CARM1 with Various Substrates.,Boriack-Sjodin PA, Jin L, Jacques SL, Drew A, Sneeringer C, Scott MP, Moyer MP, Ribich S, Moradei O, Copeland RA ACS Chem Biol. 2015 Nov 23. PMID:26551522[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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