E3 ubiquitin-protein ligase TRIM21 (TRIM21)
The protein contains 475 amino acids for an estimated molecular weight of 54170 Da.
E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B ('Thr-187' phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is t (updated: April 1, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs1042302 | |
| dbSNP:rs58403334 | |
| dbSNP:rs2975162 | |
| dbSNP:rs2554934 |
Biological Process
Cell cycle
Cytokine-mediated signaling pathway
Innate immune response
Interferon-gamma-mediated signaling pathway
Negative regulation of innate immune response
Negative regulation of NF-kappaB transcription factor activity
Negative regulation of protein deubiquitination
Negative regulation of viral release from host cell
Negative regulation of viral transcription
Positive regulation of autophagy
Positive regulation of cell cycle
Positive regulation of DNA-binding transcription factor activity
Positive regulation of I-kappaB kinase/NF-kappaB signaling
Positive regulation of NF-kappaB transcription factor activity
Positive regulation of protein binding
Positive regulation of type I interferon production
Positive regulation of viral entry into host cell
Protein autoubiquitination
Protein destabilization
Protein K63-linked ubiquitination
Protein monoubiquitination
Protein polyubiquitination
Protein trimerization
Protein ubiquitination
Regulation of gene expression
Regulation of protein localization
Regulation of type I interferon production
Regulation of viral entry into host cell
Response to interferon-gamma
The reference OMIM entry for this protein is 109092
Tripartite motif-containing protein 21; trim21
Sjogren syndrome antigen a1; ssa1
Sicca syndrome antigen a; ssa
Autoantigen ro/ssa, 52-kd; ro52
CLONING
Ro/SSA is a ribonucleoprotein particle composed of a single polypeptide and 1 of 4 small RNA molecules. Autoantibodies to Ro/SSA are present in 30 to 50% of patients with systemic lupus erythematosus (SLE; 152700) and in at least half of patients with primary Sjogren syndrome (270150). At least 2 distinct Ro/SSA polypeptides exist, a 60-kD form (TROVE2; 600063) and a 52-kD form. Using serum from a lupus patient to screen a human thymocyte cDNA expression library, Itoh et al. (1991) cloned TRIM21, which encodes the 52-kD Ro/SSA antigen. The deduced 475-amino acid protein has a calculated molecular mass of 54.1 kD. It has multiple N-terminal zinc finger motifs, a central leucine zipper, and a potential N-glycosylation site. Predicted hydrophobic regions are located at the N terminus, in the center of the molecule, and at the C terminus. Western blot analysis of lymphocyte extracts using patient serum confirmed that TRIM21 had an apparent molecular mass of 52 kD. James et al. (2007) stated that the human TRIM21 protein contains an N-terminal RING finger that has E3 ligase activity, followed by a B box, 2 coiled-coil regions, and a long C-terminal PRYSPRY domain that binds IgG (see 147100) Fc fragments.GENE FUNCTION
Frank (1999) found that human RO52 expressed in insect cells bound double-stranded but not single-stranded DNA, and that zinc was required for binding. Sequencing oligonucleotides bound by RO52 revealed a purine-rich consensus motif, ARGRGGG(G/C)(A/C)GRNGA, in which R represents a purine and N indicates no consensus.BIOCHEMICAL FEATURES
James et al. (2007) solved the crystal structure of the TRIM21 PRYSPRY domain in complex with Fc to 2.35-angstrom resolution. The PRYSPRY binding surface was formed by 6 extended loops, and mutation analysis showed that asp355, trp381, trp383, and phe450 were required for Fc binding. PRYSPRY bound the CH2-CH3 site of Fc, and the stoichiometry was 2 molecules of PRYSPRY to 1 Fc fragment. Binding between PRYSPRY and Fc was independent of pH from pH 8 to pH 5, but it was highly salt sensitive. James et al. (2007) hypothesized that during autoimmune disease, anti-TRIM21 antibodies bind epitopes in the RING and B-box domains of TRIM21 via their antigen-binding fragment (Fab) and also bind to the PRYSPRY domain of TRIM21 via their Fc portions. Simultaneous binding of Fab and Fc to TRIM21 is likely to occur between distinct TRIM21 molecules via an antibody bipolar bridging mechanism, a feature of pathogenic superantigens, and form large crosslinked immune complexes.GENE STRUCTURE
Frank et al. (1993) determined that the TRIM21 gene contains at least 3 exons. The exon encoding the putative zinc fingers of the protein is separate from that encoding the leucine zipper.MAPPING
By radioisotopic in situ hybridization, Frank et al. (1993) mapped the TRIM21 gene to chromosome 11p15.5.MOLECULAR GENETICS
Frank et al. (1993) identified a RFLP of the TRIM21 gene and demonstrated that it was associated with SLE, primarily in black Americans. ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 109092 was added.
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed