ID ACTN4_HUMAN Reviewed; 911 AA. AC O43707; A4K467; D6PXK4; O76048; DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot. DT 21-FEB-2001, sequence version 2. DT 27-MAR-2024, entry version 250. DE RecName: Full=Alpha-actinin-4 {ECO:0000305}; DE AltName: Full=Non-muscle alpha-actinin 4 {ECO:0000303|PubMed:10656685}; GN Name=ACTN4 {ECO:0000312|HGNC:HGNC:166}; 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). RC TISSUE=Neuroblastoma; RX PubMed=10656685; DOI=10.1038/sj.onc.1203310; RA Nikolopoulos S.N., Spengler B.A., Kisselbach K., Evans A.E., Biedler J.L., RA Ross R.A.; RT "The human non-muscle alpha-actinin protein encoded by the ACTN4 gene RT suppresses tumorigenicity of human neuroblastoma cells."; RL Oncogene 19:380-386(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ACTN4ISO), SUBCELLULAR LOCATION, AND RP ALTERNATIVE SPLICING. RX PubMed=22567897; RA Aksenova V.I.U., Khotin M.G., Turoverova L.V., Iudintseva N.M., RA Magnusson K.E., Pinaev G.P., Tentler D.G.; RT "Novel splicing isoform of actin-binding protein alpha-actinin 4 in RT epidermoid carcinoma cells A431."; RL Tsitologiia 54:25-32(2012). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3). RA Chakraborty S., Cheng X., Lam M., Reineke E.L., Li X., Liu Y., Gao C., RA Khurana S., Kao H.-Y.; RT "Actinin alpha4, an actin binding protein, is a transcriptional coactivator RT that antagonizes class II HDAC activity."; RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases. RN [4] 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Placenta; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-170 (ISOFORM 1). RC TISSUE=Uterus; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-224 (ISOFORM 1). RX PubMed=16344560; DOI=10.1101/gr.4039406; RA Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T., Yamashita R., RA Yamamoto J., Sekine M., Tsuritani K., Wakaguri H., Ishii S., Sugiyama T., RA Saito K., Isono Y., Irie R., Kushida N., Yoneyama T., Otsuka R., Kanda K., RA Yokoi T., Kondo H., Wagatsuma M., Murakawa K., Ishida S., Ishibashi T., RA Takahashi-Fujii A., Tanase T., Nagai K., Kikuchi H., Nakai K., Isogai T., RA Sugano S.; RT "Diversification of transcriptional modulation: large-scale identification RT and characterization of putative alternative promoters of human genes."; RL Genome Res. 16:55-65(2006). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-911 (ISOFORM 1), FUNCTION, SUBCELLULAR RP LOCATION, AND TISSUE SPECIFICITY. RX PubMed=9508771; DOI=10.1083/jcb.140.6.1383; RA Honda K., Yamada T., Endo R., Ino Y., Gotoh M., Tsuda H., Yamada Y., RA Chiba H., Hirohashi S.; RT "Actinin-4, a novel actin-bundling protein associated with cell motility RT and cancer invasion."; RL J. Cell Biol. 140:1383-1393(1998). RN [9] RP ERRATUM OF PUBMED:9508771. RA Honda K., Yamada T., Endo R., Ino Y., Gotoh M., Tsuda H., Yamada Y., RA Chiba H., Hirohashi S.; RL J. Cell Biol. 143:276-276(1998). RN [10] RP INTERACTION WITH MAGI1. RX PubMed=12042308; DOI=10.1074/jbc.m203072200; RA Patrie K.M., Drescher A.J., Welihinda A., Mundel P., Margolis B.; RT "Interaction of two actin-binding proteins, synaptopodin and alpha-actinin- RT 4, with the tight junction protein MAGI-1."; RL J. Biol. Chem. 277:30183-30190(2002). RN [11] RP FUNCTION, AND IDENTIFICATION IN THE CART COMPLEX. RX PubMed=15772161; DOI=10.1091/mbc.e04-11-1014; RA Yan Q., Sun W., Kujala P., Lotfi Y., Vida T.A., Bean A.J.; RT "CART: an Hrs/actinin-4/BERP/myosin V protein complex required for RT efficient receptor recycling."; RL Mol. Biol. Cell 16:2470-2482(2005). RN [12] RP IDENTIFICATION IN A MRNP GRANULE COMPLEX, IDENTIFICATION BY MASS RP SPECTROMETRY, AND SUBCELLULAR LOCATION. RX PubMed=17289661; DOI=10.1074/mcp.m600346-mcp200; RA Joeson L., Vikesaa J., Krogh A., Nielsen L.K., Hansen T., Borup R., RA Johnsen A.H., Christiansen J., Nielsen F.C.; RT "Molecular composition of IMP1 ribonucleoprotein granules."; RL Mol. Cell. Proteomics 6:798-811(2007). RN [13] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-114; LYS-592 AND LYS-625, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-249, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [17] RP INTERACTION WITH SEPTIN14. RX PubMed=33228246; DOI=10.3390/biomedicines8110518; RA Lin Y.H., Huang C.Y., Ke C.C., Wang Y.Y., Lai T.H., Liu H.C., Ku W.C., RA Chan C.C., Lin Y.H.; RT "ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects."; RL Biomedicines 8:0-0(2020). RN [18] RP STRUCTURE BY NMR OF 519-645. RA Kowalski K., Merkel A.L., Booker G.W.; RT "Solution structure of the third spectrin repeat of alpha-actinin-4."; RL Submitted (JUN-2004) to the PDB data bank. RN [19] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 734-757 IN COMPLEX WITH VCL, AND RP INTERACTION WITH VCL. RX PubMed=15988023; DOI=10.1128/mcb.25.14.6112-6122.2005; RA Bois P.R.J., Borgon R.A., Vonrhein C., Izard T.; RT "Structural dynamics of alpha-actinin-vinculin interactions."; RL Mol. Cell. Biol. 25:6112-6122(2005). RN [20] RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 47-271, AND CHARACTERIZATION OF RP VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262. RX PubMed=18164029; DOI=10.1016/j.jmb.2007.11.084; RA Lee S.H., Weins A., Hayes D.B., Pollak M.R., Dominguez R.; RT "Crystal structure of the actin-binding domain of alpha-actinin-4 Lys255Glu RT mutant implicated in focal segmental glomerulosclerosis."; RL J. Mol. Biol. 376:317-324(2008). RN [21] RP CHARACTERIZATION OF VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262, FUNCTION, RP INTERACTION WITH PPARG AND RARA, MUTAGENESIS OF 87-LEU-LEU-88, DOMAIN, AND RP SUBCELLULAR LOCATION. RX PubMed=22351778; DOI=10.1074/jbc.m112.345421; RA Khurana S., Chakraborty S., Lam M., Liu Y., Su Y.T., Zhao X., Saleem M.A., RA Mathieson P.W., Bruggeman L.A., Kao H.Y.; RT "Familial focal segmental glomerulosclerosis (FSGS)-linked alpha-actinin 4 RT (ACTN4) protein mutants lose ability to activate transcription by nuclear RT hormone receptors."; RL J. Biol. Chem. 287:12027-12035(2012). RN [22] RP VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262. RC TISSUE=Lymphocyte; RX PubMed=10700177; DOI=10.1038/73456; RA Kaplan J.M., Kim S.H., North K.N., Rennke H., Correia L.A., Tong H.-Q., RA Mathis B.J., Rodriguez-Perez J.-C., Allen P.G., Beggs A.H., Pollak M.R.; RT "Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal RT segmental glomerulosclerosis."; RL Nat. Genet. 24:251-256(2000). RN [23] RP VARIANT FSGS1 PHE-262. RX PubMed=18436095; DOI=10.1053/j.ajkd.2008.01.018; RA Choi H.J., Lee B.H., Cho H.Y., Moon K.C., Ha I.S., Nagata M., Choi Y., RA Cheong H.I.; RT "Familial focal segmental glomerulosclerosis associated with an ACTN4 RT mutation and paternal germline mosaicism."; RL Am. J. Kidney Dis. 51:834-838(2008). RN [24] RP VARIANT FSGS1 GLN-310. RX PubMed=22732337; DOI=10.5414/cn107320; RA Buescher A.K., Konrad M., Nagel M., Witzke O., Kribben A., Hoyer P.F., RA Weber S.; RT "Mutations in podocyte genes are a rare cause of primary FSGS associated RT with ESRD in adult patients."; RL Clin. Nephrol. 78:47-53(2012). RN [25] RP VARIANTS FSGS1 THR-427 AND ASP-748, AND VARIANTS VAL-784; ARG-786; LEU-787; RP SER-787; TYR-793; ASP-798 AND MET-801. RX PubMed=23890478; RA Safarikova M., Reiterova J., Safrankova H., Stekrova J., Zidkova A., RA Obeidova L., Kohoutova M., Tesar V.; RT "Mutational analysis of ACTN4, encoding alpha-actinin 4, in patients with RT focal segmental glomerulosclerosis using HRM method."; RL Folia Biol. (Praha) 59:110-115(2013). RN [26] RP VARIANTS FSGS1 ARG-59; GLN-72; LEU-153; GLU-255; ILE-259 AND PRO-262. RX PubMed=23014460; DOI=10.1038/ki.2012.349; RA Barua M., Brown E.J., Charoonratana V.T., Genovese G., Sun H., Pollak M.R.; RT "Mutations in the INF2 gene account for a significant proportion of RT familial but not sporadic focal and segmental glomerulosclerosis."; RL Kidney Int. 83:316-322(2013). CC -!- FUNCTION: F-actin cross-linking protein which is thought to anchor CC actin to a variety of intracellular structures. This is a bundling CC protein (Probable). Probably involved in vesicular trafficking via its CC association with the CART complex. The CART complex is necessary for CC efficient transferrin receptor recycling but not for EGFR degradation CC (PubMed:15772161). Involved in tight junction assembly in epithelial CC cells probably through interaction with MICALL2. Links MICALL2 to the CC actin cytoskeleton and recruits it to the tight junctions (By CC similarity). May also function as a transcriptional coactivator, CC stimulating transcription mediated by the nuclear hormone receptors CC PPARG and RARA (PubMed:22351778). {ECO:0000250|UniProtKB:P57780, CC ECO:0000269|PubMed:15772161, ECO:0000269|PubMed:22351778, CC ECO:0000305|PubMed:9508771}. CC -!- SUBUNIT: Homodimer; antiparallel. Binds TRIM3 at the N-terminus CC (PubMed:15772161). Interacts with MICALL2 (preferentially in opened CC conformation); stimulated by RAB13 activation (By similarity). CC Identified in a complex with CASK, IQGAP1, MAGI2, NPHS1, SPTAN1 and CC SPTBN1 (By similarity). Identified in a IGF2BP1-dependent mRNP granule CC complex containing untranslated mRNAs (PubMed:17289661). Component of CC the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 CC (PubMed:15772161). Interacts with MAGI1 (PubMed:12042308). Interacts CC with PDLIM2 (By similarity). Interacts with PPARG and RARA CC (PubMed:22351778). Binds to VCL; this interaction triggers VCL CC conformational changes (PubMed:15988023). Interacts with SEPTIN14 CC (PubMed:33228246). {ECO:0000250|UniProtKB:P57780, CC ECO:0000250|UniProtKB:Q9QXQ0, ECO:0000269|PubMed:12042308, CC ECO:0000269|PubMed:15772161, ECO:0000269|PubMed:15988023, CC ECO:0000269|PubMed:17289661, ECO:0000269|PubMed:22351778, CC ECO:0000269|PubMed:33228246}. CC -!- INTERACTION: CC O43707; Q08043: ACTN3; NbExp=3; IntAct=EBI-351526, EBI-2880652; CC O43707; A8K571: BMP7; NbExp=3; IntAct=EBI-351526, EBI-10174327; CC O43707; Q9NWQ9: C14orf119; NbExp=3; IntAct=EBI-351526, EBI-725606; CC O43707; P35222: CTNNB1; NbExp=7; IntAct=EBI-351526, EBI-491549; CC O43707; P46940: IQGAP1; NbExp=4; IntAct=EBI-351526, EBI-297509; CC O43707; O60294: LCMT2; NbExp=3; IntAct=EBI-351526, EBI-11023122; CC O43707; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-351526, EBI-739832; CC O43707; P50222: MEOX2; NbExp=3; IntAct=EBI-351526, EBI-748397; CC O43707; Q8IY33: MICALL2; NbExp=3; IntAct=EBI-351526, EBI-2555563; CC O43707; Q9NPC6: MYOZ2; NbExp=16; IntAct=EBI-351526, EBI-746712; CC O43707; O00151: PDLIM1; NbExp=3; IntAct=EBI-351526, EBI-724897; CC O43707; O94875-10: SORBS2; NbExp=4; IntAct=EBI-351526, EBI-12037893; CC O43707; Q07157: TJP1; NbExp=4; IntAct=EBI-351526, EBI-79553; CC O43707; B2R8Y4; NbExp=3; IntAct=EBI-351526, EBI-10175581; CC O43707; P03466: NP; Xeno; NbExp=2; IntAct=EBI-351526, EBI-2547640; CC O43707; Q5L4H4: NP; Xeno; NbExp=5; IntAct=EBI-351526, EBI-9512099; CC O43707-1; P10276: RARA; NbExp=2; IntAct=EBI-15971664, EBI-413374; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:22351778, CC ECO:0000269|PubMed:9508771}. Cytoplasm {ECO:0000269|PubMed:22351778, CC ECO:0000269|PubMed:9508771}. Cell junction CC {ECO:0000250|UniProtKB:P57780}. Cytoplasm, cytoskeleton, stress fiber CC {ECO:0000269|PubMed:9508771}. Cytoplasm, perinuclear region CC {ECO:0000250|UniProtKB:P57780}. Note=Localized in cytoplasmic mRNP CC granules containing untranslated mRNAs. Expressed in the perinuclear CC rim and manchette structure in early elongating spermatids during CC spermiogenesis (By similarity). Nuclear translocation can be induced by CC the PI3 kinase inhibitor wortmannin or by cytochalasin D. Exclusively CC localized in the nucleus in a limited number of cell lines (breast CC cancer cell line MCF-7, oral floor cancer IMC-2, and bladder cancer KU- CC 7). {ECO:0000250|UniProtKB:P57780, ECO:0000269|PubMed:17289661, CC ECO:0000269|PubMed:9508771}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O43707-1; Sequence=Displayed; CC Name=ACTN4ISO; CC IsoId=O43707-2; Sequence=VSP_047733; CC Name=3; CC IsoId=O43707-3; Sequence=VSP_053401; CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:9508771}. CC -!- DOMAIN: Contains one Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif that mediates CC interaction with nuclear receptors. {ECO:0000269|PubMed:22351778}. CC -!- DISEASE: Focal segmental glomerulosclerosis 1 (FSGS1) [MIM:603278]: A CC renal pathology defined by the presence of segmental sclerosis in CC glomeruli and resulting in proteinuria, reduced glomerular filtration CC rate and progressive decline in renal function. Renal insufficiency CC often progresses to end-stage renal disease, a highly morbid state CC requiring either dialysis therapy or kidney transplantation. CC {ECO:0000269|PubMed:10700177, ECO:0000269|PubMed:18164029, CC ECO:0000269|PubMed:18436095, ECO:0000269|PubMed:22351778, CC ECO:0000269|PubMed:22732337, ECO:0000269|PubMed:23014460, CC ECO:0000269|PubMed:23890478}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform ACTN4ISO]: Does not colocalize with actin CC cytoskeleton structures. {ECO:0000269|PubMed:22567897}. CC -!- SIMILARITY: Belongs to the alpha-actinin family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC17470.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAA24447.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; 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; U48734; AAC17470.1; ALT_FRAME; mRNA. DR EMBL; GU987085; ADG03678.1; -; mRNA. DR EMBL; DQ431186; ABD96103.1; -; mRNA. DR EMBL; AC008649; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC022144; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC005033; AAH05033.1; -; mRNA. DR EMBL; AL047603; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AU118403; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; D89980; BAA24447.1; ALT_INIT; mRNA. DR CCDS; CCDS12518.1; -. [O43707-1] DR RefSeq; NP_004915.2; NM_004924.5. [O43707-1] DR PDB; 1WLX; NMR; -; A=519-645. DR PDB; 1YDI; X-ray; 1.80 A; B=734-757. DR PDB; 2R0O; X-ray; 2.20 A; A/B=47-271. DR PDB; 6O31; X-ray; 1.51 A; A=47-271. DR PDB; 6OA6; X-ray; 1.37 A; A=47-271. DR PDBsum; 1WLX; -. DR PDBsum; 1YDI; -. DR PDBsum; 2R0O; -. DR PDBsum; 6O31; -. DR PDBsum; 6OA6; -. DR AlphaFoldDB; O43707; -. DR BMRB; O43707; -. DR SMR; O43707; -. DR BioGRID; 106596; 378. DR CORUM; O43707; -. DR DIP; DIP-33179N; -. DR IntAct; O43707; 126. DR MINT; O43707; -. DR STRING; 9606.ENSP00000252699; -. DR CarbonylDB; O43707; -. DR GlyGen; O43707; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O43707; -. DR MetOSite; O43707; -. DR PhosphoSitePlus; O43707; -. DR SwissPalm; O43707; -. DR BioMuta; ACTN4; -. DR REPRODUCTION-2DPAGE; O43707; -. DR CPTAC; CPTAC-7; -. DR CPTAC; CPTAC-8; -. DR EPD; O43707; -. DR jPOST; O43707; -. DR MassIVE; O43707; -. DR MaxQB; O43707; -. DR PaxDb; 9606-ENSP00000252699; -. DR PeptideAtlas; O43707; -. DR PRIDE; O43707; -. DR ProteomicsDB; 12838; -. DR ProteomicsDB; 49125; -. [O43707-1] DR Pumba; O43707; -. DR Antibodypedia; 974; 565 antibodies from 42 providers. DR DNASU; 81; -. DR Ensembl; ENST00000252699.7; ENSP00000252699.2; ENSG00000130402.14. [O43707-1] DR Ensembl; ENST00000390009.7; ENSP00000439497.1; ENSG00000130402.14. [O43707-2] DR Ensembl; ENST00000634692.1; ENSP00000488962.1; ENSG00000282844.2. [O43707-2] DR Ensembl; ENST00000634960.2; ENSP00000489220.1; ENSG00000282844.2. [O43707-1] DR GeneID; 81; -. DR KEGG; hsa:81; -. DR MANE-Select; ENST00000252699.7; ENSP00000252699.2; NM_004924.6; NP_004915.2. DR UCSC; uc002oja.3; human. [O43707-1] DR AGR; HGNC:166; -. DR CTD; 81; -. DR DisGeNET; 81; -. DR GeneCards; ACTN4; -. DR HGNC; HGNC:166; ACTN4. DR HPA; ENSG00000130402; Low tissue specificity. DR MalaCards; ACTN4; -. DR MIM; 603278; phenotype. DR MIM; 604638; gene. DR neXtProt; NX_O43707; -. DR OpenTargets; ENSG00000130402; -. DR Orphanet; 656; Genetic steroid-resistant nephrotic syndrome. DR PharmGKB; PA23; -. DR VEuPathDB; HostDB:ENSG00000130402; -. DR eggNOG; KOG0035; Eukaryota. DR GeneTree; ENSGT00940000159343; -. DR HOGENOM; CLU_005217_1_1_1; -. DR InParanoid; O43707; -. DR OMA; KTIMSYM; -. DR OrthoDB; 2872403at2759; -. DR PhylomeDB; O43707; -. DR TreeFam; TF352676; -. DR PathwayCommons; O43707; -. DR Reactome; R-HSA-114608; Platelet degranulation. DR Reactome; R-HSA-373753; Nephrin family interactions. DR SignaLink; O43707; -. DR SIGNOR; O43707; -. DR BioGRID-ORCS; 81; 24 hits in 1168 CRISPR screens. DR ChiTaRS; ACTN4; human. DR EvolutionaryTrace; O43707; -. DR GeneWiki; Actinin_alpha_4; -. DR GenomeRNAi; 81; -. DR Pharos; O43707; Tbio. DR PRO; PR:O43707; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; O43707; Protein. DR Bgee; ENSG00000130402; Expressed in popliteal artery and 101 other cell types or tissues. DR ExpressionAtlas; O43707; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:UniProtKB. DR GO; GO:0030054; C:cell junction; IBA:GO_Central. DR GO; GO:0042995; C:cell projection; IBA:GO_Central. DR GO; GO:0030864; C:cortical actin cytoskeleton; IBA:GO_Central. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB. DR GO; GO:0005925; C:focal adhesion; HDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0031143; C:pseudopodium; TAS:UniProtKB. DR GO; GO:1990904; C:ribonucleoprotein complex; IDA:UniProtKB. DR GO; GO:0001725; C:stress fiber; IEA:UniProtKB-SubCell. DR GO; GO:0030018; C:Z disc; IBA:GO_Central. DR GO; GO:0003779; F:actin binding; TAS:UniProtKB. DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. DR GO; GO:0031490; F:chromatin DNA binding; IDA:UniProtKB. DR GO; GO:0005178; F:integrin binding; TAS:UniProtKB. DR GO; GO:0016922; F:nuclear receptor binding; IPI:UniProtKB. DR GO; GO:0030374; F:nuclear receptor coactivator activity; IMP:UniProtKB. DR GO; GO:0042974; F:nuclear retinoic acid receptor binding; IPI:UniProtKB. DR GO; GO:0001882; F:nucleoside binding; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0003713; F:transcription coactivator activity; IMP:UniProtKB. DR GO; GO:0044325; F:transmembrane transporter binding; IPI:UniProtKB. DR GO; GO:0030036; P:actin cytoskeleton organization; IBA:GO_Central. DR GO; GO:0055001; P:muscle cell development; IBA:GO_Central. DR GO; GO:1900025; P:negative regulation of substrate adhesion-dependent cell spreading; IMP:UniProtKB. DR GO; GO:0035357; P:peroxisome proliferator activated receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:UniProtKB. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0032417; P:positive regulation of sodium:proton antiporter activity; NAS:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:UniProtKB. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB. DR GO; GO:0048384; P:retinoic acid receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB. DR GO; GO:0030050; P:vesicle transport along actin filament; IMP:UniProtKB. DR CDD; cd21214; CH_ACTN_rpt1; 1. DR CDD; cd21216; CH_ACTN_rpt2; 1. DR CDD; cd00051; EFh; 1. DR CDD; cd00176; SPEC; 3. DR Gene3D; 1.20.58.60; -; 4. DR Gene3D; 1.10.418.10; Calponin-like domain; 2. DR Gene3D; 1.10.238.10; EF-hand; 2. DR IDEAL; IID00129; -. DR InterPro; IPR001589; Actinin_actin-bd_CS. DR InterPro; IPR001715; CH_dom. DR InterPro; IPR036872; CH_dom_sf. DR InterPro; IPR011992; EF-hand-dom_pair. DR InterPro; IPR014837; EF-hand_Ca_insen. DR InterPro; IPR018247; EF_Hand_1_Ca_BS. DR InterPro; IPR002048; EF_hand_dom. DR InterPro; IPR018159; Spectrin/alpha-actinin. DR InterPro; IPR002017; Spectrin_repeat. DR PANTHER; PTHR11915:SF425; ALPHA-ACTININ-4; 1. DR PANTHER; PTHR11915; SPECTRIN/FILAMIN RELATED CYTOSKELETAL PROTEIN; 1. DR Pfam; PF00307; CH; 2. DR Pfam; PF08726; EFhand_Ca_insen; 1. DR Pfam; PF00435; Spectrin; 4. DR SMART; SM00033; CH; 2. DR SMART; SM00054; EFh; 2. DR SMART; SM01184; efhand_Ca_insen; 1. DR SMART; SM00150; SPEC; 4. DR SUPFAM; SSF47576; Calponin-homology domain, CH-domain; 1. DR SUPFAM; SSF47473; EF-hand; 1. DR SUPFAM; SSF46966; Spectrin repeat; 4. DR PROSITE; PS00019; ACTININ_1; 1. DR PROSITE; PS00020; ACTININ_2; 1. DR PROSITE; PS50021; CH; 2. DR PROSITE; PS00018; EF_HAND_1; 1. DR PROSITE; PS50222; EF_HAND_2; 2. DR Genevisible; O43707; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Actin-binding; Alternative splicing; Calcium; KW Cell junction; Cytoplasm; Cytoskeleton; Disease variant; Metal-binding; KW Nucleus; Phosphoprotein; Protein transport; Reference proteome; Repeat; KW Transport. FT CHAIN 1..911 FT /note="Alpha-actinin-4" FT /id="PRO_0000073440" FT DOMAIN 50..154 FT /note="Calponin-homology (CH) 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00044" FT DOMAIN 163..269 FT /note="Calponin-homology (CH) 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00044" FT REPEAT 293..403 FT /note="Spectrin 1" FT /evidence="ECO:0000255" FT REPEAT 413..518 FT /note="Spectrin 2" FT /evidence="ECO:0000255" FT REPEAT 528..639 FT /note="Spectrin 3" FT /evidence="ECO:0000255" FT REPEAT 649..752 FT /note="Spectrin 4" FT /evidence="ECO:0000255" FT DOMAIN 765..800 FT /note="EF-hand 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT DOMAIN 806..841 FT /note="EF-hand 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT REGION 1..269 FT /note="Actin-binding" FT REGION 12..26 FT /note="Interaction with VCL" FT /evidence="ECO:0000269|PubMed:15988023, FT ECO:0007744|PDB:1YDI" FT REGION 40..61 FT /note="Interaction with VCL" FT /evidence="ECO:0000269|PubMed:15988023, FT ECO:0007744|PDB:1YDI" FT REGION 108..126 FT /note="Interaction with VCL" FT /evidence="ECO:0000269|PubMed:15988023, FT ECO:0007744|PDB:1YDI" FT REGION 177..192 FT /note="Polyphosphoinositide (PIP2)-binding" FT /evidence="ECO:0000255" FT REGION 736..911 FT /note="Mediates interaction with MICALL2" FT /evidence="ECO:0000250|UniProtKB:P57780" FT MOTIF 84..88 FT /note="LXXLL motif" FT /evidence="ECO:0000269|PubMed:22351778" FT BINDING 778 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 780 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT BINDING 789 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448" FT MOD_RES 31 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P12814" FT MOD_RES 114 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 214 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P12814" FT MOD_RES 249 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 592 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 625 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 696 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P12814" FT MOD_RES 779 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P57780" FT MOD_RES 859 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P57780" FT MOD_RES 909 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Z1P2" FT VAR_SEQ 54..272 FT /note="Missing (in isoform ACTN4ISO)" FT /evidence="ECO:0000303|PubMed:22567897" FT /id="VSP_047733" FT VAR_SEQ 89..478 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_053401" FT VARIANT 59 FT /note="W -> R (in FSGS1)" FT /evidence="ECO:0000269|PubMed:23014460" FT /id="VAR_079797" FT VARIANT 72 FT /note="E -> Q (in FSGS1)" FT /evidence="ECO:0000269|PubMed:23014460" FT /id="VAR_079798" FT VARIANT 153 FT /note="F -> L (in FSGS1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:23014460" FT /id="VAR_079799" FT VARIANT 255 FT /note="K -> E (in FSGS1; no effect on protein abundance; no FT effect on homodimerization; loss of localization to the FT nucleus; prevents nuclear localization of the wild-type FT protein; decreased interaction with PPARG and RARA; loss of FT transcriptional coactivator activity; dominant negative FT effect on nuclear receptors-mediated transcription; FT increased actin-binding affinity; dbSNP:rs121908415)" FT /evidence="ECO:0000269|PubMed:10700177, FT ECO:0000269|PubMed:18164029, ECO:0000269|PubMed:22351778, FT ECO:0000269|PubMed:23014460" FT /id="VAR_010378" FT VARIANT 259 FT /note="T -> I (in FSGS1; no effect on protein abundance; no FT effect on homodimerization; loss of localization to the FT nucleus; prevents nuclear localization of the wild-type FT protein; decreased interaction with PPARG and RARA; loss of FT transcriptional coactivator activity; dominant negative FT effect on nuclear receptors-mediated transcription; FT increased actin-binding affinity; dbSNP:rs121908416)" FT /evidence="ECO:0000269|PubMed:10700177, FT ECO:0000269|PubMed:18164029, ECO:0000269|PubMed:22351778, FT ECO:0000269|PubMed:23014460" FT /id="VAR_010379" FT VARIANT 262 FT /note="S -> F (in FSGS1)" FT /evidence="ECO:0000269|PubMed:18436095" FT /id="VAR_072115" FT VARIANT 262 FT /note="S -> P (in FSGS1; no effect on protein abundance; no FT effect on homodimerization; loss of localization to the FT nucleus; prevents nuclear localization of the wild-type FT protein; decreased interaction with PPARG and RARA; loss of FT transcriptional coactivator activity; dominant negative FT effect on nuclear receptors-mediated transcription; FT increased actin-binding affinity; dbSNP:rs121908417)" FT /evidence="ECO:0000269|PubMed:10700177, FT ECO:0000269|PubMed:18164029, ECO:0000269|PubMed:22351778, FT ECO:0000269|PubMed:23014460" FT /id="VAR_010380" FT VARIANT 310 FT /note="R -> Q (in FSGS1; uncertain significance; FT dbSNP:rs112545413)" FT /evidence="ECO:0000269|PubMed:22732337" FT /id="VAR_079800" FT VARIANT 427 FT /note="A -> T (in FSGS1; dbSNP:rs201128110)" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072116" FT VARIANT 748 FT /note="N -> D (in FSGS1)" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072117" FT VARIANT 784 FT /note="A -> V (found in patients with IgA nephropathy; FT uncertain significance; dbSNP:rs771421233)" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072118" FT VARIANT 786 FT /note="G -> R" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072119" FT VARIANT 787 FT /note="P -> L" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072120" FT VARIANT 787 FT /note="P -> S" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072121" FT VARIANT 793 FT /note="C -> Y (found in patients with IgA nephropathy; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072122" FT VARIANT 798 FT /note="G -> D (found in patients with IgA nephropathy; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072123" FT VARIANT 801 FT /note="V -> M (in dbSNP:rs141727248)" FT /evidence="ECO:0000269|PubMed:23890478" FT /id="VAR_072124" FT MUTAGEN 87..88 FT /note="LL->AA: Reduced interaction with RARA. Loss of the FT transcriptional coac tivator activity toward RARA." FT /evidence="ECO:0000269|PubMed:22351778" FT CONFLICT 60 FT /note="C -> S (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 164 FT /note="S -> L (in Ref. 6; AL047603)" FT /evidence="ECO:0000305" FT CONFLICT 221 FT /note="V -> F (in Ref. 7; AU118403)" FT /evidence="ECO:0000305" FT CONFLICT 276 FT /note="T -> TET (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 292..294 FT /note="EHL -> CSTS (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 359..360 FT /note="TL -> SV (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 476 FT /note="I -> S (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 526 FT /note="I -> II (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 536 FT /note="R -> P (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 645 FT /note="Q -> QQ (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 673..674 FT /note="GR -> A (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 850 FT /note="A -> T (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT CONFLICT 891..893 FT /note="AVP -> GVR (in Ref. 1; AAC17470)" FT /evidence="ECO:0000305" FT HELIX 47..64 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 65..67 FT /evidence="ECO:0007829|PDB:6OA6" FT TURN 74..80 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 82..92 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 105..121 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 131..136 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 139..154 FT /evidence="ECO:0007829|PDB:6OA6" FT TURN 155..157 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 165..177 FT /evidence="ECO:0007829|PDB:6OA6" FT STRAND 187..189 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 190..192 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 196..205 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 207..209 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 212..214 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 220..234 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 243..248 FT /evidence="ECO:0007829|PDB:6OA6" FT STRAND 249..251 FT /evidence="ECO:0007829|PDB:6O31" FT HELIX 254..268 FT /evidence="ECO:0007829|PDB:6OA6" FT HELIX 519..552 FT /evidence="ECO:0007829|PDB:1WLX" FT HELIX 560..600 FT /evidence="ECO:0007829|PDB:1WLX" FT STRAND 606..608 FT /evidence="ECO:0007829|PDB:1WLX" FT HELIX 616..641 FT /evidence="ECO:0007829|PDB:1WLX" FT HELIX 736..756 FT /evidence="ECO:0007829|PDB:1YDI" SQ SEQUENCE 911 AA; 104854 MW; 461580C3F22937D1 CRC64; MVDYHAANQS YQYGPSSAGN GAGGGGSMGD YMAQEDDWDR DLLLDPAWEK QQRKTFTAWC NSHLRKAGTQ IENIDEDFRD GLKLMLLLEV ISGERLPKPE RGKMRVHKIN NVNKALDFIA SKGVKLVSIG AEEIVDGNAK MTLGMIWTII LRFAIQDISV EETSAKEGLL LWCQRKTAPY KNVNVQNFHI SWKDGLAFNA LIHRHRPELI EYDKLRKDDP VTNLNNAFEV AEKYLDIPKM LDAEDIVNTA RPDEKAIMTY VSSFYHAFSG AQKAETAANR ICKVLAVNQE NEHLMEDYEK LASDLLEWIR RTIPWLEDRV PQKTIQEMQQ KLEDFRDYRR VHKPPKVQEK CQLEINFNTL QTKLRLSNRP AFMPSEGKMV SDINNGWQHL EQAEKGYEEW LLNEIRRLER LDHLAEKFRQ KASIHEAWTD GKEAMLKHRD YETATLSDIK ALIRKHEAFE SDLAAHQDRV EQIAAIAQEL NELDYYDSHN VNTRCQKICD QWDALGSLTH SRREALEKTE KQLEAIDQLH LEYAKRAAPF NNWMESAMED LQDMFIVHTI EEIEGLISAH DQFKSTLPDA DREREAILAI HKEAQRIAES NHIKLSGSNP YTTVTPQIIN SKWEKVQQLV PKRDHALLEE QSKQQSNEHL RRQFASQANV VGPWIQTKME EIGRISIEMN GTLEDQLSHL KQYERSIVDY KPNLDLLEQQ HQLIQEALIF DNKHTNYTME HIRVGWEQLL TTIARTINEV ENQILTRDAK GISQEQMQEF RASFNHFDKD HGGALGPEEF KACLISLGYD VENDRQGEAE FNRIMSLVDP NHSGLVTFQA FIDFMSRETT DTDTADQVIA SFKVLAGDKN FITAEELRRE LPPDQAEYCI ARMAPYQGPD AVPGALDYKS FSTALYGESD L //