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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Warmack, Rebeccah A. Clarke, Steven G. Debler, Erik W. Blobel, Günter Jain, Kanishk Stavropoulos, Pete Feng, You |
| Description | Author Affiliation: Debler EW ( Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065); Jain K ( Department of Chemistry and Biochemistry and The Molecular Biology Institute, University of California, Los Angeles, CA 90095); Warmack RA ( Department of Chemistry and Biochemistry and The Molecular Biology Institute, University of California, Los Angeles, CA 90095); Feng Y ( Department of Chemistry and Biochemistry and The Molecular Biology Institute, University of California, Los Angeles, CA 90095); Clarke SG ( Department of Chemistry and Biochemistry and The Molecular Biology Institute, University of California, Los Angeles, CA 90095); Blobel G ( Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065); Stavropoulos P ( Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065); |
| Abstract | Trypanosoma brucei PRMT7 (TbPRMT7) is a protein arginine methyltransferase (PRMT) that strictly monomethylates various substrates, thus classifying it as a type III PRMT. However, the molecular basis of its unique product specificity has remained elusive. Here, we present the structure of TbPRMT7 in complex with its cofactor product S-adenosyl-l-homocysteine (AdoHcy) at 2.8 Å resolution and identify a glutamate residue critical for its monomethylation behavior. TbPRMT7 comprises the conserved methyltransferase and ß-barrel domains, an N-terminal extension, and a dimerization arm. The active site at the interface of the N-terminal extension, methyltransferase, and ß-barrel domains is stabilized by the dimerization arm of the neighboring protomer, providing a structural basis for dimerization as a prerequisite for catalytic activity. Mutagenesis of active-site residues highlights the importance of Glu181, the second of the two invariant glutamate residues of the double E loop that coordinate the target arginine in substrate peptides/proteins and that increase its nucleophilicity. Strikingly, mutation of Glu181 to aspartate converts TbPRMT7 into a type I PRMT, producing asymmetric dimethylarginine (ADMA). Isothermal titration calorimetry (ITC) using a histone H4 peptide showed that the Glu181Asp mutant has markedly increased affinity for monomethylated peptide with respect to the WT, suggesting that the enlarged active site can favorably accommodate monomethylated peptide and provide sufficient space for ADMA formation. In conclusion, these findings yield valuable insights into the product specificity and the catalytic mechanism of protein arginine methyltransferases and have important implications for the rational (re)design of PRMTs. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 8 |
| Volume Number | 113 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2016-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Aspartic Acid Chemistry Glutamic Acid Protein Multimerization Protein-Arginine N-Methyltransferases Protozoan Proteins Trypanosoma Brucei Brucei Enzymology Metabolism Crystallography, X-Ray Protein Structure, Quaternary Protein Structure, Tertiary Genetics S-Adenosylhomocysteine Substrate Specificity Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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