Biological methylation of myelin basic protein: Enzymology and biological significance

Kim, Sangduk; Lim, In Kyoung; Park, Gil Hong; Paik, Woon Ki

doi:10.1016/s1357-2725(97)00009-5

Cited by 76 publications

(62 citation statements)

References 58 publications

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“…In general, we obtained higher Mowse scores using ETD compared with CID for lysine methylated peptides. For Sul7D, the ETD and CID analysis revealed a number of previously identified sites and additional novel sites of monomethyllysine [13,30,38] (summarized in Table 1 and Supplementary Figure S4). The corresponding CID and ETD (CRCID) spectra for the doubly charged TPAG(meK)EAELVPEK peptide only generated a few backbone fragments during ETD (CRCID), whereas the CID spectrum is of considerable better quality (see Supplementary Figure S5).…”

Section: Lysine Methylation Analysis Using Cid and Etd Tandem Msmentioning

confidence: 99%

Analysis of arginine and lysine methylation utilizing peptide separations at neutral pH and electron transfer dissociation mass spectrometry

Snijders

Hung

Wilson

et al. 2010

J Am Soc Mass Spectrom

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Arginine and lysine methylation are widespread protein post-translational modifications. Peptides containing these modifications are difficult to retain using traditional reversed-phase liquid chromatography because they are intrinsically basic/hydrophilic and often fragment poorly during collision induced fragmentation (CID). Therefore, they are difficult to analyze using standard proteomic workflows. To overcome these caveats, we performed peptide separations at neutral pH, resulting in increased retention of the hydrophilic/basic methylated peptides before identification using MS/MS. Alternatively trifluoroacetic acid (TFA) was used for increased trapping of methylated peptides. Electron-transfer dissociation (ETD) mass spectrometry was then used to identify and characterize methylated residues. In contrast to previous reports utilizing ETD for arginine methylation, we observed significant amount of side-chain fragmentation. Using heavy methyl stable isotope labeling with amino acids in cell culture it was shown that, similar to CID, a loss of monomethylamine or dimethylamine from the arginine methylated side-chain during ETD can be used as a diagnostic to determine the type of arginine methylation. CID of lysine methylated peptides does not lead to significant neutral losses, but ETD is still beneficial because of the high charge states of such peptides. The developed LC MS/MS methods were successfully applied to tryptic digests of a number of methylated proteins, including splicing factor proline-glutamine-rich protein (SFPQ), RNA and export factor-binding protein 2 (REF2-I) and Sul7D, demonstrating significant advantages over traditional LC MS/MS approaches. (J Am Soc Mass Spectrom 2010, 21, 88 -96)

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Section: Lysine Methylation Analysis Using Cid and Etd Tandem Msmentioning

confidence: 99%

Analysis of arginine and lysine methylation utilizing peptide separations at neutral pH and electron transfer dissociation mass spectrometry

Snijders

Hung

Wilson

et al. 2010

J Am Soc Mass Spectrom

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“…One of the possible causes might be inhibition of myelin basic protein-arginine N-methyltransferase (Kim et al 1997), resulting in abnormal methylation of myelin basic protein, an important constituent of myelin. It has been shown that 100-fold elevation of AdoHcy decreases the activity of this methyltransferase by about 90% (Ghosh et al 1988).…”

Section: Similarites Between Patients 1 Andmentioning

confidence: 99%

S‐Adenosylhomocysteine hydrolase deficiency: A second patient, the younger brother of the index patient, and outcomes during therapy

Barić

Ćuk

Fumić

et al. 2005

J of Inher Metab Disea

116

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SummaryS-Adenosylhomocysteine (AdoHcy) hydrolase deficiency has been proven in a human only once, in a recently described Croatian boy. Here we report the clinical course and biochemical abnormalities of the younger brother of this proband. This younger brother has the same two mutations in the gene encoding AdoHcy hydrolase, and has been monitored since birth. We report, as well, outcomes during therapy for both patients. The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination). The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology. The latter include, most importantly, markedly elevated plasma AdoHcy. Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life). The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine.*Correspondence: Department of Pediatrics, University Hospital Center, Kišpatićeva 12, Rebro, 10000 Zagreb, Croatia. E-mail: ibaric@kbc-zagreb.hr. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptS-Adenosylhomocysteine (AdoHcy) hydrolase (adenosylhomocysteinase, EC 3.3.1.1) is the enzyme that catalyses hydrolysis of AdoHcy to adenosine and homocysteine (De La Haba and Cantoni 1959). Its deficiency (McKusick 180960) had been proven in a human only once, in a Croatian boy we reported recently (Barić et al 2004). The index patient presented with myopathy, characterized by hypotonia and delayed psychomotor development from birth, abnormally slow brain myelination (noted in MRI studies of the brain at 12.7 months) and mild hepatitis-like findings. The main biochemical abnormalities were marked increases of creatine kinase and aminotransferases, prolonged prothrombin time, low albumin, and specific amino acid aberrations indicative of the aetiology: hypermethioninaemia with almost normal total plasma homocysteine and very elevated plasma AdoHcy (up to 150 × normal) and SAdenosylmethionine (AdoMet) (up to 30 times normal). Activity of AdoHcy hydrolase was severely diminished: about 3% of control in liver and 9−15% of the mean controls in fibroblasts and red blood cells. The specific metabolic defect had been identified and the patient started on therapy by age 12.8 months. Here we report a second patient (patient 2), a brother of the proband. Patient 2 has been monitored since birth and was started on therapy at age 3.4 months, by which time the diagnosis of AdoHcy hydrolase deficiency had been clearly established. We report, also, outcomes during therapy in both patients. METHODS Metabolite assaysAmino acids were measured by i...

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“…Methyla-tion of MBP by vitamin B 12 administration reversed the myelinolysis of subacute combined degeneration of the spinal cord, suggesting an important role for methylation in myelination (16). A role for arginine methylation in signaling and transcriptional activation has been postulated (17)(18)(19)(20).…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

“…Dimethylation was 2.21 Ϯ 1.06 in the normal and 3.21 Ϯ 2.74 in the MS samples. Because methylation of MBP has been reported to be essential for the formation of compact myelin (16), the increased methylation in MS probably reflects attempts at remyelination, which fails in the demyelinating environment. Alternatively, the apparent increase in methylation may reflect the increased resistance of MBP imparted on it by methylation, e.g.…”

Section: Table IV Deamidation Of Glutamine In Mbp Charge Isomers Frommentioning

confidence: 99%

Multiple Sclerosis

Kim

Mastronardi

Wood

et al. 2003

Molecular & Cellular Proteomics

179

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Myelin basic protein (MBP) represents a candidate autoantigen in multiple sclerosis (MS). We isolated MBP from normal and MS human white matter and purified six components (charge isomers) to compare the post-translational modifications on each. The sites and extent of methylation, deimination, and phosphorylation were documented for all tryptic peptides by mass spectrometry. We found that mono and dimethylated arginine 107 was increased in MS samples; deimination of arginine occurred at a number of sites and was elevated in MS; phosphorylation was observed in 10 peptides in normal samples but was greatly reduced or absent in most peptides from MS samples. Data obtained with MBP isolated from fresh brain obtained from a spontaneously demyelinating mouse model supported the view that the changes observed in human brain were probably related to pathogenesis of demyelination, i.e. we found decreased phosphorylation and decreased amounts of glycogen synthesis kinase in brain homogenates using specific antibodies. This study represents the first to define post-translational modifications in demyelinating disease and suggest an important role in pathogenesis. Molecular & Cellular Proteomics 2:453-462, 2003. Multiple sclerosis (MS)1 is the most common demyelinating disease of the human central nervous system. It is multifactorial, requiring genetic, environmental (possibly viral), and immunological factors (1). Genetic screens of MS populations have failed to uncover a major susceptibility locus (2), suggesting that MS is a polygenic disease with each gene of small effect.Myelin basic protein (MBP), a major myelin protein that accounts for 35% of the total myelin protein, is a strong candidate autoantigen (3). It is a 170-amino acid protein in the human, containing 19 arginyl and 12 lysyl residues, which accounts for its basic character. It is devoid of cysteinyl residues, with a high proportion of disorder promoting amino acids such as A, R, G, Q, S, P, E, and K. It is a member of an expanding group of proteins that include the amyloid and prion proteins, considered to be intrinsically disordered (4), in which the disordered state is the functional state. Because of this, post-translational modifications determine the nature and extent of secondary structure, permitting the protein to adopt multiple conformations for a variety of binding events (5). Because interactions between the positive arginyl and lysyl residues and the negatively charged phosphate groups of the membrane phospholipids are essential to the structure of compact myelin, changes in positive charge of MBP would decrease the strength of these interactions (6).MBP is an unusual protein that has never been crystallized due to the myriad of post-translational modifications it possesses. These include phosphorylation, deamidation, deimination, arginine methylation, and N-terminal acylation. These give rise to a family of microheteromers or "charge isomers," several of which can be resolved by chromatography (7). The effects of some of these modifications o...

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Biological methylation of myelin basic protein: Enzymology and biological significance

Cited by 76 publications

References 58 publications

Analysis of arginine and lysine methylation utilizing peptide separations at neutral pH and electron transfer dissociation mass spectrometry

Analysis of arginine and lysine methylation utilizing peptide separations at neutral pH and electron transfer dissociation mass spectrometry

S‐Adenosylhomocysteine hydrolase deficiency: A second patient, the younger brother of the index patient, and outcomes during therapy

Multiple Sclerosis

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