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J. Biol. Chem., Vol. 280, Issue 28, 26094-26098, July 15, 2005

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Protein L-Isoaspartyl Methyltransferase Catalyzes in Vivo Racemization of Aspartate-25 in Mammalian Histone H2B^*

Glen W. Young, Sarah A. Hoofring, Mark J. Mamula, Hester A. Doyle, Gerard J. Bunick¶, Yonglin Hu¶, and Dana W. Aswad||

From the Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, the Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, and the ^¶University of Tennessee-Oak Ridge Graduate School of Genome Science and Technology, Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831

Protein L-isoaspartyl methyltransferase (PIMT) has been implicated in the repair or metabolism of proteins containing atypical L-isoaspartyl peptide bonds. The repair hypothesis is supported by previous studies demonstrating in vitro repair of isoaspartyl peptides via formation of a succinimide intermediate. Utilization of this mechanism in vivo predicts that PIMT modification sites should exhibit significant racemization as a side reaction to the main repair pathway. We therefore studied the D/L ratio of aspartic acid at specific sites in histone H2B, a known target of PIMT in vivo. Using H2B from canine brain, we found that Asp²⁵ (the major PIMT target site in H2B) was significantly racemized, exhibiting D/L ratios as high as 0.12, whereas Asp⁵¹, a comparison site, exhibited negligible racemization (D/L 0.01). Racemization of Asp²⁵ was independent of animal age over the range of 2–15 years. Using H2B from 2–3-week mouse brain, we found a similar D/L ratio (0.14) at Asp²⁵ in wild type mice, but substantially less racemization (D/L = 0.035) at Asp²⁵ in PIMT-deficient mice. These findings suggest that PIMT functions in the repair, rather than the metabolic turnover, of isoaspartyl proteins in vivo. Because PIMT has numerous substrates in cells, these findings also suggest that D-aspartate may be more common in cellular proteins than hitherto imagined and that its occurrence, in some proteins at least, is independent of animal age.

Received for publication, April 4, 2005 , and in revised form, May 19, 2005.

^* This work was supported by grants from the National Institutes of Health (to D. W. A., G. J. B., and M. J. M.), the National Aeronautics and Space Administration (to G. J. B), and the Arthritis Foundation (to M. J. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 949-824-6866; Fax: 949-824-8551; E-mail: dwaswad{at}uci.edu.

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				J. X. Zhu, H. A. Doyle, M. J. Mamula, and D. W. Aswad Protein Repair in the Brain, Proteomic Analysis of Endogenous Substrates for Protein L-Isoaspartyl Methyltransferase in Mouse Brain J. Biol. Chem., November 3, 2006; 281(44): 33802 - 33813. [Abstract] [Full Text] [PDF]