The C-terminal RG Dipeptide Repeats of the Spliceosomal Sm Proteins D1 and D3 Contain Symmetrical Dimethylarginines, Which Form a Major B-cell Epitope for Anti-Sm Autoantibodies

Brahms, Hero; Raymackers, Jos; Union, Ann; Keyser, Filip De; Meheus, Lydie; Lührmann, Reinhard

doi:10.1074/jbc.m000300200

Cited by 272 publications

(232 citation statements)

References 57 publications

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“…The data from the (GR)-repeat portion of the D3 polypeptide, its similarity to D1, and the cross-reactivity of affinity-purified anti-D3 Abs with this region of D1 seem to support the theory of crossreactivity explaining the appearance of some autoantibodies. An additional group has shown that this same region of Sm D1 is antigenic when the alternating arginines are dimethylated (35). Interestingly, this posttranslational modification may not be absolutely required for antigenicity of these sequences, as has been shown by this and other works (8,(33)(34).…”

Section: Discussionmentioning

confidence: 55%

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

McClain

Ramsland

Kaufman

et al. 2002

The Journal of Immunology

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Autoantibodies directed against spliceosomal proteins are a common and specific feature of systemic lupus erythematosus. These autoantibodies target a collection of proteins, including Sm B, B′, D1, D2, and D3. We define the common antigenic targets of Sm D2 and D3 and examine their role in spliceosomal autoimmunity. Our results define nine major common epitopes, five on Sm D2 and four on Sm D3. These epitopes have significantly higher (more basic) isoelectric points than do nonantigenic regions. In fact, this association is of sufficient power to make isoelectric point an excellent predictor of spliceosomal antigenicity. The crystallographic structure of Sm D2 and D3 is now partially described. The anti-Sm D2 and D3 antigenic targets are located on the surface of the respective three-dimensional complexed proteins, thereby suggesting that these epitopes are accessible in the native configuration. All but one of these nine epitopes conspicuously avoid the specific regions involved in intermolecular interactions within the spliceosomal complex. One of the D3 epitopes (RGRGRGMGR) has significant sequence homology with a major antigenic region of Sm D1 (containing a carboxyl-terminal glycine-arginine repeat), and anti-D3 Abs cross-react with this epitope of Sm D1. These results demonstrate that spliceosomal targets of autoimmunity are accessible on native structure surfaces and that cross-reactive epitopes, as well as structural associations of various spliceosomal Ags, may be involved in the induction of autoimmunity in systemic lupus.

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Section: Discussionmentioning

confidence: 55%

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

McClain

Ramsland

Kaufman

et al. 2002

The Journal of Immunology

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“…Anti-Sm antibodies, in vertebrates, are known to react with the Sm proteins B/BЈ, D1, and D3 (Lehmeier et al 1990), which contain symmetrical dimethyl arginine modifications on their RG-rich C-terminal tails (Brahms et al 2000(Brahms et al , 2001. However, by using the Y12 antibody, we could only detect the B/BЈ and D1 proteins, not D3, on Western blots of nuclear extracts from human 293-T cells (Fig.…”

Section: Drosophila Lsm10 and Lsm11 Interact With Each Other And Withmentioning

confidence: 75%

Evolutionary conservation of the U7 small nuclear ribonucleoprotein inDrosophila melanogaster

Azzouz

Schümperli²

2003

RNA

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The U7 snRNP involved in histone RNA 3 end processing is related to but biochemically distinct from spliceosomal snRNPs. In vertebrates, the Sm core structure assembling around the noncanonical Sm-binding sequence of U7 snRNA contains only five of the seven standard Sm proteins. The missing Sm D1 and D2 subunits are replaced by U7-specific Sm-like proteins Lsm10 and Lsm11, at least the latter of which is important for histone RNA processing. So far, it was unknown if this special U7 snRNP composition is conserved in invertebrates. Here we describe several putative invertebrate Lsm10 and Lsm11 orthologs that display low but clear sequence similarity to their vertebrate counterparts. Immunoprecipitation studies in Drosophila S2 cells indicate that the Drosophila Lsm10 and Lsm11 orthologs (dLsm10 and dLsm11) associate with each other and with Sm B, but not with Sm D1 and D2. Moreover, dLsm11 associates with the recently characterized Drosophila U7 snRNA and, indirectly, with histone H3 pre-mRNA. Furthermore, dLsm10 and dLsm11 can assemble into U7 snRNPs in mammalian cells. These experiments demonstrate a strong evolutionary conservation of the unique U7 snRNP composition, despite a high degree of primary sequence divergence of its constituents. Therefore, Drosophila appears to be a suitable system for further genetic studies of the cell biology of U7 snRNPs.

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“…In addition, the SmD1 and SmD3 lack the C-terminal RG dipeptide repeats of the human homologues (30). The arginine in this domain is methylated in the mammalian protein, constituting an important determinant of the Sm epitope (33). The lack of these modifications on the trypanosome proteins may partly explain why the trypanosome Sm proteins are not recognized by the Sm antibodies (28).…”

mentioning

confidence: 94%

Identification and Functional Characterization of Lsm Proteins in Trypanosoma brucei

Liu¹,

Liang²,

Uliel

et al. 2004

Journal of Biological Chemistry

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RNA interference of Sm proteins inTrypanosoma brucei demonstrated that the stability of the small nuclear RNAs (U1, U2, U4, U5) and the spliced leader RNA, but not U6 RNA, were affected upon Sm depletion (Mandelboim, M., Barth, S., Biton, M., Liang, X. H., and Michaeli, S. (2003) J. Biol. Chem. 278, 51469-51478), suggesting that Lsm proteins that bind and stabilize U6 RNA in other eukaryotes should exist in trypanosomes. In this study, we identified seven Lsm proteins (Lsm2p to Lsm8p) and examined the function of Lsm3p and Lsm8p by RNA interference silencing. Both Lsm proteins were found to be essential for U6 stability and mRNA decay. Silencing was lethal, and cisand trans-splicing were inhibited. Importantly, silencing also affected the level of U4.U6 and the U4.U6/U5 tri-small nuclear ribonucleoprotein complexes. The presence of Lsm proteins in trypanosomes that diverged early in the eukaryotic lineage suggests that these proteins are highly conserved in both structure and function among eukaryotes. Interestingly, however, Lsm1p that is specific to the mRNA decay complex was not identified in the genome data base of any kinetoplastidae, and the Lsm8p that in other eukaryotes exclusively functions in U6 stability was found to function in trypanosomes also in mRNA decay. These data therefore suggest that in trypanosomes only a single Lsm complex may exist.

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The C-terminal RG Dipeptide Repeats of the Spliceosomal Sm Proteins D1 and D3 Contain Symmetrical Dimethylarginines, Which Form a Major B-cell Epitope for Anti-Sm Autoantibodies

Cited by 272 publications

References 57 publications

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

Evolutionary conservation of the U7 small nuclear ribonucleoprotein inDrosophila melanogaster

Identification and Functional Characterization of Lsm Proteins in Trypanosoma brucei

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