Localization of Methylated Arginine in the A1 Protein from Myelin

Brostoff, Steven W.; Eylar, E.H.

doi:10.1073/pnas.68.4.765

Cited by 134 publications

(65 citation statements)

References 16 publications

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“…As indicated by the present study, sulphatide interacts principally with basic residues on the C-terminal region of the basic protein. For basic-protein molecules in the hairpin form (Brostoff & Eylar, 1971) the net effect would be that the hydrophilic/hydrophobic boundary of the sulphatide (the sphingosine hydroxyl and the acyl-group hydroxyl and amide bond; Clowes et al, 1971) would be positioned at the N-terminal section of the basic protein, where non-polar amino acid residues at discrete sites of this part of the polypeptide chain could associate with sulphatide acyl chains by hydrophobic interactions. Such an arrangement is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Localization of sites for ionic interaction with lipid in the C-terminal third of the bovine myelin basic protein

Jones¹,

Rumsby²

1977

Biochemical Journal

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The myelin basic protein from bovine brain tissue was purified and the two peptides obtained by cleavage of the polypeptide chain at the single tryptophan residue were isolated. The interaction of these peptides and the intact basic protein with complex lipids was investigated by following the solubilization of lipid-protein complexes into chloroform in a biphasic solvent system. The C-terminal peptide fragment (residues 117-170) and the intact basic protein both formed chloroform-soluble complexes with acidic lipids, but not with neutral complex lipids. The N-terminal fragment (residues 1-115) did not form chloroform-soluble complexes with either acidic or neutral complex lipids. The molar ratio of lipid to protein that caused a 50 % loss of protein from the upper phase to the lower chloroform phase was the same for the intact basic protein as for the smaller C-terminal peptide fragment. Phosphatidylserine and phosphatidylinositol were approximately twice as efficient as sulphatide at causing protein redistribution to the chloroform phase. The results are interpreted as indicating that the sites for ionic interactions between lipid and charged groups on the basic protein of myelin are located in the C-terminal region of the protein molecule.

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Section: Resultsmentioning

confidence: 99%

Localization of sites for ionic interaction with lipid in the C-terminal third of the bovine myelin basic protein

Jones¹,

Rumsby²

1977

Biochemical Journal

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“…First, arginine methylation could regulate protein-protein interactions. As an example, researchers have speculated that the methylation of myelin basic proteins (MBPs) helps to stabilize the insertion into the myelin sheath (11,14). Second, this modification could serve to modulate the RNA-binding activity.…”

Section: Discussionmentioning

confidence: 99%

A Novel Methyltransferase (Hmt1p) Modifies Poly(A)⁺-RNA-Binding Proteins

Henry

Silver

1996

Molecular and Cellular Biology

159

161

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RNA-binding proteins play many essential roles in the metabolism of nuclear pre-mRNA. As such, they demonstrate a myriad of dynamic behaviors and modifications. In particular, heterogeneous nuclear ribonucleoproteins (hnRNPs) contain the bulk of methylated arginine residues in eukaryotic cells. We have identified the first eukaryotic hnRNP-specific methyltransferase via a genetic screen for proteins that interact with an abundant poly(A) ؉ -RNA-binding protein termed Npl3p. We have previously shown that npl3-1 mutants are temperature sensitive for growth and defective for export of mRNA from the nucleus. New mutants in interacting genes were isolated by their failure to survive in the presence of the npl3-1 allele. Four alleles of the same gene were identified in this manner. Cloning of the cognate gene revealed an encoded protein with similarity to methyltransferases that was termed HMT1 for hnRNP methyltransferase. HMT1 is not required for normal cell viability except when NPL3 is also defective. The Hmt1 protein is located in the nucleus. We demonstrate that Npl3p is methylated by Hmt1p both in vivo and in vitro. These findings now allow further exploration of the function of this previously uncharacterized class of enzymes.The primary transcripts of eukaryotic RNA polymerase II, termed heterogeneous nuclear RNAs or pre-mRNAs, undergo a series of processing events in nuclei as they mature into functional, cytoplasmic mRNAs. Prominent among these events are 5Ј-end capping (43), splicing (29, 58), modification of individual bases (15), 3Ј-end cleavage coupled to polyadenylation (30, 37), and export of the processed mRNA to the cytoplasm (20, 35). When pre-mRNAs emerge from the transcription complex and throughout the time they are in nuclei, they are associated with an array of nuclear factors, including heterogeneous nuclear ribonucleoproteins (hnRNPs) and small nuclear RNP particles. Numerous studies have established the roles of small nuclear RNPs in a variety of nuclear processes, such as pre-mRNA splicing (2, 31, 58). However, the functions of hnRNPs have remained unclear; they are proposed to function in nearly all the known steps of mRNA maturation, including pre-mRNA packaging (17, 66), constitutive and alternate splicing (13, 49), and mRNA export (26,42,53).Proteins of partially purified mammalian hnRNP particles contain a high level of the unusual modified amino acid N Protein arginine methyltransferases specific for hnRNP A1 have been identified and partially purified from three different sources: calf brain (28), rat liver (55) and HeLa cells (46). All three enzymes use S-adenosyl-L-methionine (SAM) as the methyl donor and have similar enzymatic properties. Further characterization of these enzymes indicates that their substrates are not limited to pre-mRNA-binding proteins (hnRNPs) (46,51,55). Rather, they have activities toward a wide range of RNA-binding proteins, all of which appear to contain the RGG box RNA-binding motif (6,38).Given the prevalence of this unusual modification in hnRNPs, it is...

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“…The effects of other modifications such as methylation of arginine 107 as the mono-methyl or symmetric dimethyl arginine (14,15) have not been studied as extensively. 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).…”

Section: Multiple Sclerosis (Ms)mentioning

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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Localization of Methylated Arginine in the A1 Protein from Myelin

Cited by 134 publications

References 16 publications

Localization of sites for ionic interaction with lipid in the C-terminal third of the bovine myelin basic protein

Localization of sites for ionic interaction with lipid in the C-terminal third of the bovine myelin basic protein

A Novel Methyltransferase (Hmt1p) Modifies Poly(A)⁺-RNA-Binding Proteins

Multiple Sclerosis

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Localization of Methylated Arginine in the A1 Protein from Myelin

Cited by 134 publications

References 16 publications

Localization of sites for ionic interaction with lipid in the C-terminal third of the bovine myelin basic protein

Localization of sites for ionic interaction with lipid in the C-terminal third of the bovine myelin basic protein

A Novel Methyltransferase (Hmt1p) Modifies Poly(A)+-RNA-Binding Proteins

Multiple Sclerosis

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Product

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A Novel Methyltransferase (Hmt1p) Modifies Poly(A)⁺-RNA-Binding Proteins