ID RFXK_HUMAN Reviewed; 260 AA. AC O14593; O95839; Q24JQ1; Q6FGA8; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 15-JUL-1999, sequence version 2. DT 27-MAR-2024, entry version 208. DE RecName: Full=DNA-binding protein RFXANK; DE AltName: Full=Ankyrin repeat family A protein 1; DE AltName: Full=Regulatory factor X subunit B; DE Short=RFX-B; DE AltName: Full=Regulatory factor X-associated ankyrin-containing protein; GN Name=RFXANK; Synonyms=ANKRA1, RFXB; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), IDENTIFICATION BY MASS RP SPECTROMETRY, FUNCTION, AND INVOLVEMENT IN BLS2. RC TISSUE=B-cell; RX PubMed=9806546; DOI=10.1038/3081; RA Masternak K., Barras E., Zufferey M., Conrad B., Corthals G., Aebersold R., RA Sanchez J.-C., Hochstrasser D.F., Mach B., Reith W.; RT "A gene encoding a novel RFX-associated transactivator is mutated in the RT majority of MHC class II deficiency patients."; RL Nat. Genet. 20:273-277(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), PROTEIN SEQUENCE OF 79-95; RP 180-198; 100-210 AND 238-248, FUNCTION (ISOFORMS 1 AND 2), AND INVOLVEMENT RP IN BLS2. RC TISSUE=Lymphoblast; RX PubMed=10072068; DOI=10.1016/s1074-7613(00)80016-3; RA Nagarajan U.M., Louis-Plence P., DeSandro A., Nilsen R., Bushey A., RA Boss J.M.; RT "RFX-B is the gene responsible for the most common cause of the bare RT lymphocyte syndrome, an MHC class II immunodeficiency."; RL Immunity 10:153-162(1999). RN [3] RP ERRATUM OF PUBMED:10072068. RA Nagarajan U.M., Louis-Plence P., DeSandro A., Nilsen R., Bushey A., RA Boss J.M.; RL Immunity 10:399-399(1999). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Umbilical cord blood; RX PubMed=11042152; DOI=10.1101/gr.140200; RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G., RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W., RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.; RT "Cloning and functional analysis of cDNAs with open reading frames for 300 RT previously undefined genes expressed in CD34+ hematopoietic stem/progenitor RT cells."; RL Genome Res. 10:1546-1560(2000). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP SUBUNIT. RX PubMed=20732328; DOI=10.1016/j.jmb.2010.08.025; RA Laird K.M., Briggs L.L., Boss J.M., Summers M.F., Garvie C.W.; RT "Solution structure of the heterotrimeric complex between the interaction RT domains of RFX5 and RFXAP from the RFX gene regulatory complex."; RL J. Mol. Biol. 403:40-51(2010). RN [10] RP INTERACTION WITH RFX7. RX PubMed=25752541; DOI=10.1016/j.str.2015.02.001; RA Nie J., Xu C., Jin J., Aka J.A., Tempel W., Nguyen V., You L., Weist R., RA Min J., Pawson T., Yang X.J.; RT "Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome RT protein CCDC8."; RL Structure 23:700-712(2015). RN [11] RP X-RAY CRYSTALLOGRAPHY (1.57 ANGSTROMS) OF 90-260 IN COMPLEX WITH RFX5 RP PEPTIDE, CHARACTERIZATION OF VARIANT BLS2 PRO-195, AND MUTAGENESIS OF RP ASP-121 AND TYR-224. RX PubMed=22649097; DOI=10.1126/scisignal.2002979; RA Xu C., Jin J., Bian C., Lam R., Tian R., Weist R., You L., Nie J., RA Bochkarev A., Tempel W., Tan C.S., Wasney G.A., Vedadi M., Gish G.D., RA Arrowsmith C.H., Pawson T., Yang X.J., Min J.; RT "Sequence-specific recognition of a PxLPxI/L motif by an ankyrin repeat RT tumbler lock."; RL Sci. Signal. 5:RA39-RA39(2012). RN [12] RP X-RAY CRYSTALLOGRAPHY (1.78 ANGSTROMS) OF 90-260 IN COMPLEX WITH RFX7. RA Tempel W., Xu C., Dong A., Li Y., Bountra C., Arrowsmith C.H., RA Edwards A.M., Min J.; RT "Crystal structure of RFXANK ankyrin repeats in complex with RFX7."; RL Submitted (JUN-2014) to the PDB data bank. RN [13] RP VARIANT BLS2 PRO-195, AND FUNCTION. RX PubMed=10725724; DOI=10.4049/jimmunol.164.7.3666; RA Nagarajan U.M., Peijnenburg A., Gobin S.J., Boss J.M., van den Elsen P.J.; RT "Novel mutations within the RFX-B gene and partial rescue of MHC and RT related genes through exogenous class II transactivator in RFX-B-deficient RT cells."; RL J. Immunol. 164:3666-3674(2000). CC -!- FUNCTION: Activates transcription from class II MHC promoters. CC Activation requires the activity of the MHC class II CC transactivator/CIITA. May regulate other genes in the cell. RFX binds CC the X1 box of MHC-II promoters (PubMed:9806546, PubMed:10072068, CC PubMed:10725724). May also potentiate the activation of RAF1 (By CC similarity). {ECO:0000250|UniProtKB:Q9Z205, CC ECO:0000269|PubMed:10072068, ECO:0000269|PubMed:10725724, CC ECO:0000269|PubMed:9806546}. CC -!- FUNCTION: Isoform 2 is not involved in the positive regulation of MHC CC class II genes. {ECO:0000269|PubMed:10072068}. CC -!- SUBUNIT: Forms homodimers (By similarity). The RFX heterotetrameric CC complex consists of 2 molecules of RFX5 and one each of RFXAP and RFX- CC B/RFXANK; with each subunit representing a separate complementation CC group. Interacts (via ankyrin repeats) with RFX5 (via PxLPxI/L motif); CC the interaction is direct. RFX forms cooperative DNA binding complexes CC with X2BP and CBF/NF-Y. RFX associates with CIITA to form an active CC transcriptional complex (PubMed:20732328, PubMed:22649097). Interacts CC with RAF1 (By similarity). Interacts (via ankyrin repeats) with RFX7 CC (via PxLPxI/L motif) (PubMed:25752541). {ECO:0000250|UniProtKB:Q9Z205, CC ECO:0000269|PubMed:20732328, ECO:0000269|PubMed:22649097, CC ECO:0000269|PubMed:25752541, ECO:0000312|PDB:6MEW}. CC -!- INTERACTION: CC O14593; P48382: RFX5; NbExp=8; IntAct=EBI-1057665, EBI-923266; CC O14593; Q2KHR2: RFX7; NbExp=2; IntAct=EBI-1057665, EBI-1222187; CC O14593; O00287: RFXAP; NbExp=3; IntAct=EBI-1057665, EBI-3929296; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Z205}. Nucleus CC {ECO:0000250|UniProtKB:Q9Z205}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Long; CC IsoId=O14593-1; Sequence=Displayed; CC Name=2; Synonyms=RFX-B-delta5; CC IsoId=O14593-2; Sequence=VSP_000283, VSP_000284, VSP_054618; CC Name=3; CC IsoId=O14593-3; Sequence=VSP_000284; CC -!- TISSUE SPECIFICITY: Ubiquitous. CC -!- DOMAIN: Interacts with RAF1 via its C-terminal ankyrin repeat domain. CC The same domain also mediates its homodimerization (By similarity). The CC third ankyrin repeat is required for association with the two other RFX CC subunits; RFX5 and RFXAP. The three central ANK repeats mediate binding CC to the PxLPxI/L motif of RFX5 (PubMed:20732328, PubMed:22649097). CC {ECO:0000250|UniProtKB:Q9Z205, ECO:0000269|PubMed:20732328, CC ECO:0000269|PubMed:22649097}. CC -!- PTM: Phosphorylated by RAF1. {ECO:0000250|UniProtKB:Q9Z205}. CC -!- DISEASE: Bare lymphocyte syndrome 2 (BLS2) [MIM:209920]: A severe CC combined immunodeficiency disease with early onset. It is characterized CC by a profound defect in constitutive and interferon-gamma induced MHC CC II expression, absence of cellular and humoral T-cell response to CC antigen challenge, hypogammaglobulinemia and impaired antibody CC production. The consequence include extreme susceptibility to viral, CC bacterial and fungal infections. {ECO:0000269|PubMed:10072068, CC ECO:0000269|PubMed:10725724, ECO:0000269|PubMed:22649097, CC ECO:0000269|PubMed:9806546}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- WEB RESOURCE: Name=RFXANKbase; Note=RFXANK mutation db; CC URL="http://structure.bmc.lu.se/idbase/RFXANKbase/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF094760; AAC69883.1; -; mRNA. DR EMBL; AF105427; AAD17972.1; -; mRNA. DR EMBL; AF105428; AAD17973.1; -; mRNA. DR EMBL; AF077196; AAD26991.1; -; mRNA. DR EMBL; CR542199; CAG46996.1; -; mRNA. DR EMBL; AC002126; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC003110; AAB86654.1; -; Genomic_DNA. DR EMBL; CH471106; EAW84795.1; -; Genomic_DNA. DR EMBL; BC114558; AAI14559.1; -; mRNA. DR EMBL; BC114563; AAI14564.1; -; mRNA. DR CCDS; CCDS12395.1; -. [O14593-1] DR CCDS; CCDS62611.1; -. [O14593-3] DR RefSeq; NP_001265656.1; NM_001278727.1. [O14593-3] DR RefSeq; NP_001265657.1; NM_001278728.1. DR RefSeq; NP_003712.1; NM_003721.3. [O14593-1] DR RefSeq; NP_604389.1; NM_134440.2. DR RefSeq; XP_005260191.1; XM_005260134.4. [O14593-1] DR RefSeq; XP_005260192.1; XM_005260135.3. DR RefSeq; XP_016882904.1; XM_017027415.1. DR RefSeq; XP_016882905.1; XM_017027416.1. DR PDB; 3UXG; X-ray; 1.85 A; A=90-260. DR PDB; 3V30; X-ray; 1.57 A; A=90-260. DR PDB; 6MEW; X-ray; 1.78 A; A/C=90-260. DR PDBsum; 3UXG; -. DR PDBsum; 3V30; -. DR PDBsum; 6MEW; -. DR AlphaFoldDB; O14593; -. DR SMR; O14593; -. DR BioGRID; 114180; 166. DR ComplexPortal; CPX-6461; RFX gene regulatory complex. DR CORUM; O14593; -. DR ELM; O14593; -. DR IntAct; O14593; 26. DR STRING; 9606.ENSP00000305071; -. DR iPTMnet; O14593; -. DR PhosphoSitePlus; O14593; -. DR BioMuta; RFXANK; -. DR EPD; O14593; -. DR jPOST; O14593; -. DR MassIVE; O14593; -. DR MaxQB; O14593; -. DR PaxDb; 9606-ENSP00000305071; -. DR PeptideAtlas; O14593; -. DR ProteomicsDB; 48101; -. [O14593-1] DR ProteomicsDB; 48102; -. [O14593-2] DR ProteomicsDB; 61266; -. DR Pumba; O14593; -. DR Antibodypedia; 15290; 399 antibodies from 21 providers. DR DNASU; 8625; -. DR Ensembl; ENST00000303088.9; ENSP00000305071.2; ENSG00000064490.14. [O14593-1] DR Ensembl; ENST00000407360.7; ENSP00000384572.3; ENSG00000064490.14. [O14593-1] DR Ensembl; ENST00000456252.7; ENSP00000409138.2; ENSG00000064490.14. [O14593-3] DR GeneID; 8625; -. DR KEGG; hsa:8625; -. DR MANE-Select; ENST00000303088.9; ENSP00000305071.2; NM_003721.4; NP_003712.1. DR UCSC; uc002nls.4; human. [O14593-1] DR AGR; HGNC:9987; -. DR CTD; 8625; -. DR DisGeNET; 8625; -. DR GeneCards; RFXANK; -. DR HGNC; HGNC:9987; RFXANK. DR HPA; ENSG00000064490; Low tissue specificity. DR MalaCards; RFXANK; -. DR MIM; 209920; phenotype. DR MIM; 603200; gene. DR neXtProt; NX_O14593; -. DR OpenTargets; ENSG00000064490; -. DR Orphanet; 572; Immunodeficiency by defective expression of MHC class II. DR PharmGKB; PA34357; -. DR VEuPathDB; HostDB:ENSG00000064490; -. DR eggNOG; KOG0502; Eukaryota. DR GeneTree; ENSGT00940000160753; -. DR HOGENOM; CLU_000134_23_0_1; -. DR InParanoid; O14593; -. DR OMA; EQYMTAV; -. DR OrthoDB; 5477021at2759; -. DR PhylomeDB; O14593; -. DR TreeFam; TF333112; -. DR PathwayCommons; O14593; -. DR SignaLink; O14593; -. DR SIGNOR; O14593; -. DR BioGRID-ORCS; 8625; 26 hits in 1158 CRISPR screens. DR ChiTaRS; RFXANK; human. DR GeneWiki; RFXANK; -. DR GenomeRNAi; 8625; -. DR Pharos; O14593; Tbio. DR PRO; PR:O14593; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; O14593; Protein. DR Bgee; ENSG00000064490; Expressed in lower esophagus mucosa and 189 other cell types or tissues. DR ExpressionAtlas; O14593; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0045171; C:intercellular bridge; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:ComplexPortal. DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IPI:ARUK-UCL. DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW. DR GO; GO:0042826; F:histone deacetylase binding; IEA:Ensembl. DR GO; GO:0045348; P:positive regulation of MHC class II biosynthetic process; NAS:ComplexPortal. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:GO_Central. DR GO; GO:0007265; P:Ras protein signal transduction; IEA:Ensembl. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR IDEAL; IID00427; -. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR017362; DNA-bd_RFXANK. DR PANTHER; PTHR24124; ANKYRIN REPEAT FAMILY A; 1. DR PANTHER; PTHR24124:SF4; DNA-BINDING PROTEIN RFXANK; 1. DR Pfam; PF12796; Ank_2; 1. DR PIRSF; PIRSF038034; DNA-binding_RFXANK; 1. DR SMART; SM00248; ANK; 4. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 3. DR Genevisible; O14593; HS. PE 1: Evidence at protein level; KW 3D-structure; Activator; Alternative splicing; ANK repeat; Cytoplasm; KW Direct protein sequencing; Disease variant; DNA-binding; Nucleus; KW Reference proteome; Repeat; SCID; Transcription; Transcription regulation. FT CHAIN 1..260 FT /note="DNA-binding protein RFXANK" FT /id="PRO_0000067049" FT REPEAT 89..118 FT /note="ANK 1" FT REPEAT 123..152 FT /note="ANK 2" FT REPEAT 156..185 FT /note="ANK 3" FT REPEAT 189..218 FT /note="ANK 4" FT REPEAT 222..251 FT /note="ANK 5" FT REGION 1..79 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 53..79 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 63 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10072068" FT /id="VSP_000283" FT VAR_SEQ 91..113 FT /note="SLSIHQLAAQGELDQLKEHLRKG -> C (in isoform 2 and FT isoform 3)" FT /evidence="ECO:0000303|PubMed:10072068, FT ECO:0000303|PubMed:15489334" FT /id="VSP_000284" FT VAR_SEQ 159..172 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10072068" FT /id="VSP_054618" FT VARIANT 48 FT /note="E -> D (in dbSNP:rs34282046)" FT /id="VAR_048311" FT VARIANT 195 FT /note="L -> P (in BLS2; loss of expression; FT dbSNP:rs751386365)" FT /evidence="ECO:0000269|PubMed:10725724, FT ECO:0000269|PubMed:22649097" FT /id="VAR_009941" FT VARIANT 251 FT /note="Q -> E (in dbSNP:rs1802498)" FT /id="VAR_014472" FT MUTAGEN 121 FT /note="D->V: Loss of expression." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 224 FT /note="Y->A: Loss of interaction with RFX5." FT /evidence="ECO:0000269|PubMed:22649097" FT HELIX 94..99 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 103..110 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 115..118 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 127..133 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 137..146 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 160..166 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 170..177 FT /evidence="ECO:0007829|PDB:3V30" FT TURN 178..180 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 193..199 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 203..211 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 226..233 FT /evidence="ECO:0007829|PDB:3V30" FT HELIX 236..249 FT /evidence="ECO:0007829|PDB:3V30" SQ SEQUENCE 260 AA; 28102 MW; 6280B490F54816D2 CRC64; MELTQPAEDL IQTQQTPASE LGDPEDPGEE AADGSDTVVL SLFPCTPEPV NPEPDASVSS PQAGSSLKHS TTLTNRQRGN EVSALPATLD SLSIHQLAAQ GELDQLKEHL RKGDNLVNKP DERGFTPLIW ASAFGEIETV RFLLEWGADP HILAKERESA LSLASTGGYT DIVGLLLERD VDINIYDWNG GTPLLYAVRG NHVKCVEALL ARGADLTTEA DSGYTPMDLA VALGYRKVQQ VIENHILKLF QSNLVPADPE //