Protein Arginine Methylation in Health and Disease John M

203 Protein arginine methylation in health and disease John M. Aletta1,2,Ã and John C. Hu3 1CH3 BioSystems, LLC, University Commons (Suite 8), 1416 Sweet Home Road, Amherst, New York 14228, USA 2New York State Center of Excellence in Bioinformatics and Life Sciences Buffalo, New York, USA 3Biomedical Sciences Program, University at Buffalo, State University of New York Buffalo, New York, USA Abstract. Protein arginine methylation is a rapidly growing field of biomedical research that holds great promise for extending our understanding of developmental and pathological processes. Less than ten years ago, fewer than two dozen proteins were verified to contain methylarginine. Currently, however, hundreds of methylarginine proteins have been detected and many have been confirmed by mass spectrometry and other proteomic and molecular techniques. Several of these proteins are products of disease genes or are implicated in disease processes by recent experimental or clinical observations. The purpose of this chapter is twofold; (1) to re-examine the role of protein arginine methylation placed within the context of cell growth and differentiation, as well as within the rich variety of cellular metabolic methylation pathways and (2) to review the implications of recent advances in protein methylarginine detection and the analysis of protein methylarginine function for our understanding of human disease. Keywords: growth, differentiation, methyltransferase, proteomics, neurodevelopment, autoimmune, viral, cancer, cardiovascular. Introduction Protein methylation research can be traced back to 1939 [1], but the biomedical promise of the field has gained momentum only over the last 10–12 years. Post-translational methylations of the nucleophilic side chains of no less than eight different amino acids are known. Most common are methylation of either nitrogen or oxygen atoms, but evidence for the post- translational methylation of carbon atoms in amino acid side chains has also recently been described [2]. The N-methylation of arginine side chains is the focus of this review for two reasons. First, the diversity of the enzymatic pathways involved in the generation and modification of methylarginine proteins is broad and has grown much larger in recent years. Similarly, the discovery of a number of disease proteins that are methylated on arginine residues and the contribution of arginine methyltransferases to pathological processes forecast a broad emerging clinical relevance for protein arginine methylation. There are currently five areas of clinical medicine in which ÃCorresponding author: Tel.: (716) 688-5222. Fax: (866) 610-2261. E-mail: [email protected] (J.M. Aletta). BIOTECHNOLOGY ANNUAL REVIEW r 2008 ELSEVIER B.V. VOLUME 14 ISSN 1387-2656 ALL RIGHTS RESERVED DOI: 10.1016/S1387-2656(08)00008-2 204 protein methylation has been associated in some way with human maladies that include neurodevelopmental diseases, autoimmune disorders, and viral, neoplastic and cardiovascular disease. Advances in biochemistry, molecular genetics and proteomics have collectively accelerated the discovery and characterization of at least nine arginine methyltransferases and hundreds of arginine-methylated proteins. Type I and type II protein arginine methyltransferases (PRMTs) are responsible for catalyzing the arginine methylation of human proteins. Both types produce mono-methylarginine and the former also leads to the formation of asymmetrical dimethylarginine, while the latter produces symmetrical dimethylarginine. There are a number of recent excellent reviews that focus on PRMTs from a variety of perspectives that include the regulatory control of transcription [3], cellular functions [4], cellular signaling [5] and phylogenetic evolution and therapeutic potential [6]. When sequence analysis of in vivo asymmetric methylation sites was first performed comprehensively, a total of only 20 proteins were confirmed methylarginine proteins based on mass spectrometric analysis [7]. The generation of methylarginine-specific antibodies [8–10] has facilitated the identification and further analysis of many other methylarginine proteins. Based on a proteomic paradigm, immunopurification of symmetrical and asymmetrical dimethylarginine protein complexes revealed more than 200 putative arginine-methylated proteins [9]. Future work must, not only confirm the methylation status by alternative means, but also demonstrate that the methylation is physiologically relevant. Despite these caveats, the large number of proteins detected by this approach indicates a fundamental and widespread role of methylarginine protein in many different cellular processes that include, but are not limited to, RNA processing, transcription, cellular differentiation and DNA repair. Currently available methylarginine-specific antibodies are based on a canonical sequence motif that is derived from the glycine- and arginine-rich (GAR) domains of well-known methylproteins. Methylarginine sites in proteins without a discernible consensus motif are also well documented [11,12] and thus, expand the range of potential methylarginine proteins even further. Among the growing number of verified methylarginine proteins are many examples of disease-related proteins that can serve as methylation substrates. Methylarginine disease proteins and the potential involvement of PRMTs in human diseases will be discussed in the concluding sections of this review. Metabolic pathways The biochemical pathways that contribute to the metabolites that take part in the genesis and potential regulation of methylarginine proteins are complex (Fig. 1). The cycle of protein methylation metabolism involves chemical intermediates that play roles in many other important cellular functions, Fig. 1. The methylation metabolic cycle. The principal biochemical reaction pathways that comprise S-adenosylmethionine utilization and regeneration are illustrated. Additional reaction pathways that are not depicted include the syntheses of cyclopropane fatty acids, biotin and queuosine, a 7-deazaguanosine, hypermodified tRNA nucleoside. See text for descriptions of the pathways and the enzymes involved. ATP, adenosine triphosphate; AMP, adenosine monophosphate; PPi, inorganic pyrophosphate; Pi, inorganic phosphate; PRMT, protein arginine methyltransferase; SAM, S-adenosylmethionine; MTA, 5u-deoxy 5u-methylthioadenosine; SAH, S-adenosylhomocysteine. (The color version of this figure is hosted on Science Direct.) 206 including anti-oxidant pathways, cell growth and differentiation and the methylation of DNA, RNA and lipids, as well. For example, Fontecave et al. [13] have reviewed the unusual utilization of every chemical group of the sulfonium compound, S-adenosylmethionine (SAM). The chemical moieties of SAM participate not only in the synthesis of methylated protein, DNA, RNA and lipid (methyl group), but also in the synthesis of cyclopropyl fatty acids (methylene group), biotin (amino group), a modified nucleoside of transfer RNA (ribosyl group) and polyamines (aminopropyl group). The precursor of SAM is the essential amino acid, methionine, which is acquired principally from protein in the diet. SAM synthase, a vitamin B12-dependent enzyme, catalyzes the transfer of the adenosyl group from ATP to methionine followed by the hydrolysis of the polyphosphate to inorganic pyrophosphate and phosphate. Figure 1 illustrates the two most recognized routes for SAM metabolism, polyamine synthesis and methyl-group transfers. SAM is the sole donor of an aminopropyl group for the synthesis of the polyamines, spermidine and spermine. Following the generation of putrescine via the usual rate-limiting step of ornithine decarboxylation, the polyamines are formed from the condensation of putrescine and the aminopropyl group contributed by SAM through the action of an aminopropyl transferase. The widespread role of polyamines in cell growth, differentiation and apoptosis has been acknowl- edged for decades, but precise functions and specific mechanisms are only recently becoming somewhat clearer [14]. SAM is also the requisite source of methyl-groups for essential methylation reactions involving proteins, nucleic acids and lipids. For every methyltransferase reaction that occurs, S-adenosylhomocysteine (SAH) is generated. SAH is hydrolyzed to produce adenosine and homocysteine by the copper enzyme, SAH hydrolase. Knockout of this enzyme in the mouse is an embryonic lethal mutation. Adenosine is further metabolized within the cell to adenosine monophosphate by adenosine kinase or converted to inosine by adenosine deaminase. Ueland [15] has provided a discussion of the potential physiological implications of the adenosine route of metabolism. Homocysteine can be re-methylated to form methionine through the action of either betaine homocysteine methyltransferase (BHMT) or methylene tetrahydrofolate (THF) reductase in conjunction with methionine synthase. Alternatively, upon condensation with serine, homocysteine forms cystathionine, which is especially abundant in human brain. Cystathionine g-lyase, a vitamin B6-dependent enzyme, catalyzes the cleavage of cystathionine to yield free cysteine which can react further with glycine and glutamate to produce glutathione, a potent anti-oxidant. The relative utilization of the metabolites within each limb of the methylation metabolic cycle and the physiological significance that can be attributed to the intermediates may vary depending on the cell or tissue type, kinetic equilibria, dietary status and the developmental

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