Protein:MEFV |
Protein Summary |
 Gene summary |
| Gene name: MEFV | ASpdb.0 ID: 4210 | Gene | Gene symbol | MEFV | Gene ID | 4210 |
| Gene name | MEFV innate immunity regulator, pyrin |
| Synonyms | FMF|MEF|PAAND|TRIM20 |
| Cytomap | 16p13.3 |
| Type of gene | protein-coding |
| Description | pyrinMEFV innate immuity regulator, pyrinMEFV, pyrin innate immunity regulatorMediterranean fevermarenostrin |
| Modification date | 20240331 |
| UniProtAcc | O15553 |
| Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Gene | MEFV | GO:0003779 | actin binding | 11468188 |
| Gene | MEFV | GO:0005634 | nucleus | 11115844 |
| Gene | MEFV | GO:0005654 | nucleoplasm | - |
| Gene | MEFV | GO:0005737 | cytoplasm | 26347139 |
| Gene | MEFV | GO:0005829 | cytosol | - |
| Gene | MEFV | GO:0005875 | microtubule associated complex | 11468188 |
| Gene | MEFV | GO:0006954 | inflammatory response | 11468188 |
| Gene | MEFV | GO:0010508 | positive regulation of autophagy | 26347139 |
| Gene | MEFV | GO:0032731 | positive regulation of interleukin-1 beta production | 16037825 |
| Gene | MEFV | GO:0034341 | response to type II interferon | 26347139 |
| Gene | MEFV | GO:1904270 | pyroptosome complex assembly | 27030597 |
| Gene | MEFV | GO:2001056 | positive regulation of cysteine-type endopeptidase activity | 19158676 |
AS Summary |
| Information of the canonical protein with experimentally identified structure from PDB (2023). |
| UniProt Acc | File name | PDB ID | Method | Resolution | Chain | Start | End |
| O15553-2 | O15553-2_4cg4_A.pdb | 4CG4 | X-ray | 2.4 | A | 414 | 781 |
| ASpdb's canonical and alternatively spliced isoform information. |
| accession_id | gene_name | canonical_id | alternative_id | canonical_length | alternative_length | canonical_start | canonical_end | type | originalSEQ | variationSEQ | alternative_start | alternative_end |
| O15553 | MEFV | O15553-2 | O15553-1 | 781 | 570 | 93 | 303 | Deletion | none | none | 92 | 92 |
| O15553 | MEFV | O15553-2 | O15553-3 | 781 | 445 | 93 | 303 | Deletion | none | none | 92 | 92 |
| O15553 | MEFV | O15553-2 | O15553-3 | 781 | 445 | 587 | 781 | Substitution | VPELIGAQAHAVNVILDAETAYPNLIFSDDLKSVRLGNKWERLPDGPQRFDSCIIVLGSPSFLSGRRYWEVEVGDKTAWILGACKTSISRKGNMTLSPENGYWVVIMMKENEYQASSVPPTRLLIKEPPKRVGIFVDYRVGSISFYNVTARSHIYTFASCSFSGPLQPIFSPGTRDGGKNTAPLTICPVGGQGPD | DHSPQHGLGSWEERDYTQHSMQGPKQGVPCLSLLSGQCNLAPLNANAQDFFPYLIFLRSSGADWRSGTCC | 376 | 445 |
| Multiple sequence alignment of our canonical and alternatively spliced MEFV |
| Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of MEFV |
| UniProt-id | ENSG | ENST | ENSP |
| O15553-2 | ENSG00000103313.14 | ENST00000219596.6 | ENSP00000219596.1 |
| O15553-1 | ENSG00000103313.14 | ENST00000536379.5 | ENSP00000445079.1 |
| O15553-3 | ENSG00000103313.14 | ENST00000541159.5 | ENSP00000438711.1 |
| UniProt-id | NM ID | NP ID |
| O15553-2 | NM_000243.2 | NP_000234.1 |
| O15553-3 | NM_001198536.1 | NP_001185465.1 |
| Amino acid sequences of our canonical and alternatively spliced MEFV |
| accession_id | Protein sequence |
| O15553-2 | MAKTPSDHLLSTLEELVPYDFEKFKFKLQNTSVQKEHSRIPRSQIQRARPVKMATLLVTYYGEEYAVQLTLQVLRAINQRLLAEELHRAA IQEYSTQENGTDDSAASSSLGENKPRSLKTPDHPEGNEGNGPRPYGGGAASLRCSQPEAGRGLSRKPLSKRREKASEGLDAQGKPRTRSP ALPGGRSPGPCRALEGGQAEVRLRRNASSAGRLQGLAGGAPGQKECRPFEVYLPSGKMRPRSLEVTISTGEKAPANPEILLTLEEKTAAN LDSATEPRARPTPDGGASADLKEGPGNPEHSVTGRPPDTAASPRCHAQEGDPVDGTCVRDSCSFPEAVSGHPQASGSRSPGCPRCQDSHE RKSPGSLSPQPLPQCKRHLKQVQLLFCEDHDEPICLICSLSQEHQGHRVRPIEEVALEHKKKIQKQLEHLKKLRKSGEEQRSYGEEKAVS FLKQTEALKQRVQRKLEQVYYFLEQQEHFFVASLEDVGQMVGQIRKAYDTRVSQDIALLDALIGELEAKECQSEWELLQDIGDILHRAKT VPVPEKWTTPQEIKQKIQLLHQKSEFVEKSTKYFSETLRSEMEMFNVPELIGAQAHAVNVILDAETAYPNLIFSDDLKSVRLGNKWERLP DGPQRFDSCIIVLGSPSFLSGRRYWEVEVGDKTAWILGACKTSISRKGNMTLSPENGYWVVIMMKENEYQASSVPPTRLLIKEPPKRVGI |
| O15553-1 | MAKTPSDHLLSTLEELVPYDFEKFKFKLQNTSVQKEHSRIPRSQIQRARPVKMATLLVTYYGEEYAVQLTLQVLRAINQRLLAEELHRAA IQGRPPDTAASPRCHAQEGDPVDGTCVRDSCSFPEAVSGHPQASGSRSPGCPRCQDSHERKSPGSLSPQPLPQCKRHLKQVQLLFCEDHD EPICLICSLSQEHQGHRVRPIEEVALEHKKKIQKQLEHLKKLRKSGEEQRSYGEEKAVSFLKQTEALKQRVQRKLEQVYYFLEQQEHFFV ASLEDVGQMVGQIRKAYDTRVSQDIALLDALIGELEAKECQSEWELLQDIGDILHRAKTVPVPEKWTTPQEIKQKIQLLHQKSEFVEKST KYFSETLRSEMEMFNVPELIGAQAHAVNVILDAETAYPNLIFSDDLKSVRLGNKWERLPDGPQRFDSCIIVLGSPSFLSGRRYWEVEVGD KTAWILGACKTSISRKGNMTLSPENGYWVVIMMKENEYQASSVPPTRLLIKEPPKRVGIFVDYRVGSISFYNVTARSHIYTFASCSFSGP |
| O15553-3 | MAKTPSDHLLSTLEELVPYDFEKFKFKLQNTSVQKEHSRIPRSQIQRARPVKMATLLVTYYGEEYAVQLTLQVLRAINQRLLAEELHRAA IQGRPPDTAASPRCHAQEGDPVDGTCVRDSCSFPEAVSGHPQASGSRSPGCPRCQDSHERKSPGSLSPQPLPQCKRHLKQVQLLFCEDHD EPICLICSLSQEHQGHRVRPIEEVALEHKKKIQKQLEHLKKLRKSGEEQRSYGEEKAVSFLKQTEALKQRVQRKLEQVYYFLEQQEHFFV ASLEDVGQMVGQIRKAYDTRVSQDIALLDALIGELEAKECQSEWELLQDIGDILHRAKTVPVPEKWTTPQEIKQKIQLLHQKSEFVEKST |
Protein Functional Features |
| Main function of this protein. (from UniProt) |
| MEFV (go to UniProt):O15553 |
| Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at * Minus value of BPloci means that the break pointn is located before the CDS. |
| - Retained protein feature among the 13 regional features. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| O15553 | Domain | 580 | 775 | Note=B30.2/SPRY;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00548 | Type=Substitution;Start=587;End=781 |
| O15553 | Region | 93 | 226 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=93;End=303 |
| O15553 | Region | 93 | 226 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=93;End=303 |
| O15553 | Region | 266 | 280 | Note=Interaction with RELA;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:18577712;Dbxref=PMID:18577712 | Type=Deletion;Start=93;End=303 |
| O15553 | Region | 266 | 280 | Note=Interaction with RELA;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:18577712;Dbxref=PMID:18577712 | Type=Deletion;Start=93;End=303 |
| O15553 | Region | 270 | 322 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=93;End=303 |
| O15553 | Region | 270 | 322 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=93;End=303 |
| O15553 | Compositional bias | 93 | 115 | Note=Polar residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=93;End=303 |
| O15553 | Compositional bias | 93 | 115 | Note=Polar residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=93;End=303 |
| O15553 | Compositional bias | 154 | 171 | Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=93;End=303 |
| O15553 | Compositional bias | 154 | 171 | Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=93;End=303 |
Gene Isoform Structures and Expression Levels for MEFV |
| Gene structures of our canonical and alternative spliced genes of MEFV * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
| Expression levels of gene isoforms across GTEx. |
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| Expression levels of gene isoforms across TCGA. |
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Protein Structures |
| PDB and CIF files of the predicted protein structures * Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format. |
| 3D view using mol* of O15553-2 |
| 3D view using mol* of O15553-1 |
| 3D view using mol* of O15553-3 |
pLDDT Score Distribution |
| pLDDT score distribution of the predicted protein structures from AlphaFold2 * AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. |
| pLDDT distribution across the protein length of O15553-2 |
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| pLDDT distribution across the protein length of O15553-1 |
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| pLDDT distribution across the protein length of O15553-3 |
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Ramachandran Plot of Protein Structures |
| Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide. |
| Ramachandran plot of O15553-2 |
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| Ramachandran plot of O15553-1 |
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| Ramachandran plot of O15553-3 |
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Potential Active Site Information |
| The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite. |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| O15553-2 | 1.113 | 253 | 1.216 | 592.361 | 0.487 | 0.689 | 0.891 | 1.742 | 0.42 | 4.145 | 1.135 | 254,255,256,257,259,260,261,263,264,465,468,469,47 1,472,473,475,476,477,479,480,563,566,567,569,570, 571,573,574,577,578,581 |
| O15553-1 | 0.991 | 159 | 1.014 | 460.992 | 0.558 | 0.678 | 0.853 | 0.407 | 1.022 | 0.398 | 0.997 | 362,365,366,368,369,370,372,373,473,492,493,494,49 5,496,497,498,499,500,501,502,522,525,527,528,529, 530,531,532,533 |
| O15553-3 | 1.071 | 134 | 1.135 | 319.333 | 0.477 | 0.708 | 0.934 | 2.063 | 0.704 | 2.929 | 0.696 | 262,265,266,268,269,270,272,275,276,345,348,349,35 2,353,355,356,360,421,422,423,424,426,428,430 |
Protein Structure and Feature Comparision |
| Protein Structure Comparision Using Template Modeling Scores (TM-score). |
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| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green) |
| 3D view using mol* of O15553-2_O15553-2_4cg4_A.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of O15553-2_4cg4_A_O15553-1.pdb |
| 3D view using mol* of O15553-2_4cg4_A_O15553-3.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of O15553-2_O15553-1.pdb |
| 3D view using mol* of O15553-2_O15553-3.pdb |
| Protein Feature Comparison of the protein sequendary structures among the protiens. |
| ./stats/secondary_structure/figure/O15553-2_vs_O15553-1.png |
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| ./stats/secondary_structure/figure/O15553-2_vs_O15553-3.png |
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| Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens. |
| ./stats/relative_asa/O15553-2_vs_O15553-1.png |
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| ./stats/relative_asa/O15553-2_vs_O15553-3.png |
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Protein-Protein Interaction |
| Interactors from UniProt. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| O15553 | Region | 266 | 280 | Note=Interaction with RELA;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:18577712;Dbxref=PMID:18577712 | Type=Deletion;Start=93;End=303 |
| O15553 | Region | 266 | 280 | Note=Interaction with RELA;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:18577712;Dbxref=PMID:18577712 | Type=Deletion;Start=93;End=303 |
| Interactors from STRING. |
| Gene name | Interactors |
Related Drugs to MEFV |
| Drugs targeting this gene/protein. (DrugBank) |
| UniProt accession | Gene name | DrugBank ID | Drug name | Drug group | Actions |
Related Diseases to MEFV |
| Previous studies relating to the alternative splicing of MEFV and disease information from the MeSH term (PubMed) |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| MEFV | 11115844 | Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus. | Mutations in MEFV, a gene encoding a protein (marenostrin/pyrin) of unknown function, are associated with familial Mediterranean fever, a genetic condition characterized by febrile episodes of serosal inflammation. Based on its primary structure, this 781 residue protein is thought to function as a nuclear effector molecule. However, recent transient expression studies indicated a perinuclear cytoplasmic localization. Here, we describe the isolation and expression of a novel human MEFV isoform, MEFV-d2, generated by in-frame alternative splicing of exon 2. This transcript, expressed in leukocytes, predicts a 570 residue protein designated marenostrin-d2. To investigate differences in subcellular localization between the full-length protein (marenostrin-fl) and marenostrin-d2, while providing against the overexpression of transiently expressed proteins, we have generated CHO cell lines stably expressing these two isoforms fused to the green fluorescent protein. The localization pattern of marenostrin-d2 differs dramatically from that of marenostrin-fl. Marenostrin-fl is homogeneously distributed over the entire cytoplasm, whereas marenostrin-d2 concentrates into the nucleus. To map the critical domain(s) specifying these differences, deletion mutants have been generated. Deletion of the putative nuclear localization signals (NLS) does not alter the nuclear localization of marenostrin-d2 whereas, despite the lack of discernible NLS in the domain encoded by the exon 1-exon 3 splice junction, deletion of this domain indeed disrupts this localization. These data, which challenge the current domain organization model of marenostrin, strongly suggest that MEFV encodes a nuclear protein and raises the possibility that MEFV alternative splicing may control functions of wild-type and mutant marenostrin proteins by regulating their translocation to the nucleus. | D010505 | Familial Mediterranean Fever |
| MEFV | 19755381 | Expression of the familial Mediterranean fever gene is regulated by nonsense-mediated decay. | Mutations in the MEditerranean FeVer (MEFV) gene are responsible for familial Mediterranean fever (FMF), a recessively inherited auto-inflammatory disease. Cases of dominant inheritance and phenotype-genotype heterogeneity have been reported; however, the underlying molecular mechanism is not currently understood. The FMF protein named pyrin or marenostrin (P/M) is thought to be involved in regulating innate immunity but its function remains subject to controversy. Recent studies postulate that a defect in MEFV expression regulation may play a role in FMF physiopathology. Our group, along with others, has identified several alternatively spliced MEFV transcripts in leukocytes. Since alternative splicing and nonsense-mediated decay (NMD) pathways are usually coupled in the post-transcriptional regulation of gene expression, we hypothesized that NMD could contribute to the regulation of the MEFV gene. To address this issue, we examined the effect of indirect and direct inhibition of NMD on expression of the MEFV transcripts in THP1, monocyte and neutrophil cells. We showed that MEFV is the first auto-inflammatory gene regulated by NMD in both a cell- and transcript-specific manner. These results and preliminary western-blot analyses suggest the possible translation of alternatively spliced MEFV transcripts into several P/M variants according to cell type and inflammatory state. Our results introduce the novel hypothesis that variation of NMD efficiency could play an important role in FMF physiopathology as a potent phenotypic modifier. | D010505 | Familial Mediterranean Fever |
| MEFV | 21562927 | Enhanced exon 2 skipping caused by c.910G>A variant and alternative splicing of MEFV genes in two independent cases of familial Mediterranean fever. | Most reported cases of familial Mediterranean fever (FMF) involve missense mutations of MEFV concentrated within exon 10. We experienced two independent pedigrees of a unique variant in the MEFV gene that might cause excessive exon 2 skipping due to enhanced alternative splicing. In this study, we tried to elucidate the molecular mechanism of the MEFV variant as a cause of the FMF phenotype. Peripheral blood was obtained from volunteers and two patients with homozygous c.910G>A variant of the MEFV gene. MEFV messenger RNA (mRNA) expression patterns in mononuclear cells and granulocytes were compared using forward and reverse primers from exons 1 and 3, respectively. Expression profiles of pyrin were examined by transfecting wild-type and variant MEFV genes into HEK293T cells. Expression of normal-sized mRNA was extremely reduced in these patients, whereas that of aberrant short mRNA, deleting exon 2 (Δex2), was significantly increased. Immunohistochemical and immunoblotting analyses revealed a truncated immunoreactive pyrin protein in cells transfected with Δex2 cDNA. The MEFV gene c.910G>A variant results in accelerated aberrant splicing with abnormal protein size, presumably leading to anomalous pyrin function. This is the first report to show that an MEFV variant other than missense mutation is responsible for the FMF phenotype. | D010505 | Familial Mediterranean Fever |
| MEFV | 21562927 | Enhanced exon 2 skipping caused by c.910G>A variant and alternative splicing of MEFV genes in two independent cases of familial Mediterranean fever. | Most reported cases of familial Mediterranean fever (FMF) involve missense mutations of MEFV concentrated within exon 10. We experienced two independent pedigrees of a unique variant in the MEFV gene that might cause excessive exon 2 skipping due to enhanced alternative splicing. In this study, we tried to elucidate the molecular mechanism of the MEFV variant as a cause of the FMF phenotype. Peripheral blood was obtained from volunteers and two patients with homozygous c.910G>A variant of the MEFV gene. MEFV messenger RNA (mRNA) expression patterns in mononuclear cells and granulocytes were compared using forward and reverse primers from exons 1 and 3, respectively. Expression profiles of pyrin were examined by transfecting wild-type and variant MEFV genes into HEK293T cells. Expression of normal-sized mRNA was extremely reduced in these patients, whereas that of aberrant short mRNA, deleting exon 2 (Δex2), was significantly increased. Immunohistochemical and immunoblotting analyses revealed a truncated immunoreactive pyrin protein in cells transfected with Δex2 cDNA. The MEFV gene c.910G>A variant results in accelerated aberrant splicing with abnormal protein size, presumably leading to anomalous pyrin function. This is the first report to show that an MEFV variant other than missense mutation is responsible for the FMF phenotype. | D020022 | Genetic Predisposition to Disease |
Clinically important variants in MEFV |
| (ClinVar, 04/20/2024) |
| accession_id | uniprot_id | gene_name | Type | Variant | Clinical_significance |
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