ID IMA4_HUMAN Reviewed; 521 AA. AC O00505; O00191; O43195; Q5JVM9; Q8IYQ9; Q96AA7; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2002, sequence version 2. DT 27-MAR-2024, entry version 223. DE RecName: Full=Importin subunit alpha-4; DE AltName: Full=Importin alpha Q2; DE Short=Qip2; DE AltName: Full=Karyopherin subunit alpha-3; DE AltName: Full=SRP1-gamma; GN Name=KPNA3; Synonyms=QIP2; 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]. RC TISSUE=Fetal brain; RX PubMed=9154134; DOI=10.1159/000134521; RA Takeda S., Fujiwara T., Shimizu F., Kawai A., Shinomiya K., Okuno S., RA Ozaki K., Katagiri T., Shimada Y., Nagata M., Watanabe T., Takaichi A., RA Kuga Y., Suzuki M., Hishigaki H., Takahashi E., Shin S., Nakamura Y., RA Hirai Y.; RT "Isolation and mapping of karyopherin alpha 3 (KPNA3), a human gene that is RT highly homologous to genes encoding Xenopus importin, yeast SRP1 and human RT RCH1."; RL Cytogenet. Cell Genet. 76:87-93(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Lung; RX PubMed=9395085; DOI=10.1016/s0014-5793(97)01265-9; RA Koehler M., Ansieau S., Prehn S., Leutz A., Haller H., Hartmann E.; RT "Cloning of two novel human importin-alpha subunits and analysis of the RT expression pattern of the importin-alpha protein family."; RL FEBS Lett. 417:104-108(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9435235; DOI=10.1073/pnas.95.2.582; RA Nachury M.V., Ryder U.W., Lamond A.I., Weis K.; RT "Cloning and characterization of hSRP1 gamma, a tissue-specific nuclear RT transport factor."; RL Proc. Natl. Acad. Sci. U.S.A. 95:582-587(1998). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Fischer R.; RT "Importin alpha-3, a novel variant of the small importin subunit RT evolutionarily conserved from hydrozoa to man."; RL Submitted (MAY-1997) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057823; DOI=10.1038/nature02379; RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L., RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., RA Frankish A.G., Frankland J., French L., Garner P., Garnett J., RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., RA Rogers J., Ross M.T.; RT "The DNA sequence and analysis of human chromosome 13."; RL Nature 428:522-528(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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Muscle; 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 INTERACTION WITH INFLUENZA VIRUS NP (MICROBIAL INFECTION). RX PubMed=12740372; DOI=10.1074/jbc.m303571200; RA Melen K., Fagerlund R., Franke J., Koehler M., Kinnunen L., Julkunen I.; RT "Importin alpha nuclear localization signal binding sites for STAT1, STAT2, RT and influenza A virus nucleoprotein."; RL J. Biol. Chem. 278:28193-28200(2003). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-60, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-60, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=18318008; DOI=10.1002/pmic.200700884; RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D., RA Zou H., Gu J.; RT "Large-scale phosphoproteome analysis of human liver tissue by enrichment RT and fractionation of phosphopeptides with strong anion exchange RT chromatography."; RL Proteomics 8:1346-1361(2008). RN [13] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-56 AND SER-60, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [15] RP INTERACTION WITH HIV-1 INTEGRASE (MICROBIAL INFECTION). RX PubMed=20554775; DOI=10.1128/jvi.00508-10; RA Ao Z., Danappa Jayappa K., Wang B., Zheng Y., Kung S., Rassart E., RA Depping R., Kohler M., Cohen E.A., Yao X.; RT "Importin alpha3 interacts with HIV-1 integrase and contributes to HIV-1 RT nuclear import and replication."; RL J. Virol. 84:8650-8663(2010). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-56 AND SER-60, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [17] 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 [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-60, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-56 AND SER-60, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-56; SER-60 AND TYR-484, AND RP IDENTIFICATION BY 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 [21] RP INTERACTION WITH NCBP2 AND NCBP3. RX PubMed=26382858; DOI=10.1038/ncomms9192; RA Gebhardt A., Habjan M., Benda C., Meiler A., Haas D.A., Hein M.Y., Mann A., RA Mann M., Habermann B., Pichlmair A.; RT "mRNA export through an additional cap-binding complex consisting of NCBP1 RT and NCBP3."; RL Nat. Commun. 6:8192-8192(2015). RN [22] RP VARIANTS SPG88 ILE-315; MET-328; PRO-328; ARG-334; PRO-350 AND LEU-415, RP INVOLVEMENT IN SPG88, CHARACTERIZATION OF VARIANTS SPG88 ILE-315; MET-328; RP PRO-328; ARG-334; PRO-350 AND LEU-415, SUBCELLULAR LOCATION, AND RP INTERACTION WITH RCC1; DDX21; NCBP1 AND NCBP2. RX PubMed=34564892; DOI=10.1002/ana.26228; RA Schob C., Hempel M., Safka Brozkova D., Jiang H., Kim S.Y., Batzir N.A., RA Orenstein N., Bierhals T., Johannsen J., Uhrova Meszarosova A., Chae J.H., RA Seeman P., Woidy M., Fang F., Kubisch C., Kindler S., Denecke J.; RT "Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic RT Paraplegia."; RL Ann. Neurol. 90:738-750(2021). RN [23] RP VARIANT SPG88 ILE-315, AND INVOLVEMENT IN SPG88. RX PubMed=34981581; DOI=10.1002/ana.26297; RA De Winter J., Van de Vondel L., Zuechner S., Ortibus E., Baets J.; RT "A Recurrent KPNA3 Missense Variant Causing Infantile Pure Spastic RT Paraplegia."; RL Ann. Neurol. 91:298-299(2022). RN [24] RP VARIANT SPG88 PRO-328, AND INVOLVEMENT IN SPG88. RX PubMed=34825409; DOI=10.1002/ana.26275; RA Estiar M.A., Lail N., Dyment D.A., Varghaei P., Hartley T., Gillespie M.K., RA Yoon G., Boycott K.M., Rouleau G.A., Gan-Or Z.; RT "Heterozygous De Novo KPNA3 Mutations Cause Complex Hereditary Spastic RT Paraplegia."; RL Ann. Neurol. 91:730-732(2022). CC -!- FUNCTION: Functions in nuclear protein import as an adapter protein for CC nuclear receptor KPNB1. Binds specifically and directly to substrates CC containing either a simple or bipartite NLS motif. Docking of the CC importin/substrate complex to the nuclear pore complex (NPC) is CC mediated by KPNB1 through binding to nucleoporin FxFG repeats and the CC complex is subsequently translocated through the pore by an energy CC requiring, Ran-dependent mechanism. At the nucleoplasmic side of the CC NPC, Ran binds to importin-beta and the three components separate and CC importin-alpha and -beta are re-exported from the nucleus to the CC cytoplasm where GTP hydrolysis releases Ran from importin. The CC directionality of nuclear import is thought to be conferred by an CC asymmetric distribution of the GTP- and GDP-bound forms of Ran between CC the cytoplasm and nucleus. In vitro, mediates the nuclear import of CC human cytomegalovirus UL84 by recognizing a non-classical NLS. CC Recognizes NLSs of influenza A virus nucleoprotein probably through ARM CC repeats 7-9. CC -!- SUBUNIT: Forms a complex with importin subunit beta-1. Interacts with CC DDX21 (PubMed:34564892). Interacts with NCBP1, NCBP2/CBP20 and NCBP3 CC (PubMed:26382858, PubMed:34564892). Interacts with RCC1 CC (PubMed:34564892). {ECO:0000269|PubMed:26382858, CC ECO:0000269|PubMed:34564892}. CC -!- SUBUNIT: (Microbial infection) Interacts with HIV-1 integrase; this CC interaction might play a role in nuclear import of HIV pre-integration CC complex. {ECO:0000269|PubMed:20554775}. CC -!- SUBUNIT: (Microbial infection) Interacts with influenza virus CC nucleoprotein; this interaction might play a role in nuclear import of CC viral genome. {ECO:0000269|PubMed:12740372}. CC -!- INTERACTION: CC O00505; Q9GZX7: AICDA; NbExp=2; IntAct=EBI-358297, EBI-3834328; CC O00505; X5D778: ANKRD11; NbExp=3; IntAct=EBI-358297, EBI-17183751; CC O00505; B3KTP4: ApoL6; NbExp=3; IntAct=EBI-358297, EBI-10175904; CC O00505; Q7L5A3: ATOSB; NbExp=3; IntAct=EBI-358297, EBI-745689; CC O00505; Q8TBE0: BAHD1; NbExp=3; IntAct=EBI-358297, EBI-742750; CC O00505; Q15059-2: BRD3; NbExp=3; IntAct=EBI-358297, EBI-13468085; CC O00505; Q68D86: CCDC102B; NbExp=3; IntAct=EBI-358297, EBI-10171570; CC O00505; P46527: CDKN1B; NbExp=4; IntAct=EBI-358297, EBI-519280; CC O00505; Q9NR30: DDX21; NbExp=3; IntAct=EBI-358297, EBI-357942; CC O00505; P19447: ERCC3; NbExp=4; IntAct=EBI-358297, EBI-1183307; CC O00505; Q92731-3: ESR2; NbExp=3; IntAct=EBI-358297, EBI-12259414; CC O00505; Q86YD7: FAM90A1; NbExp=4; IntAct=EBI-358297, EBI-6658203; CC O00505; P02792: FTL; NbExp=3; IntAct=EBI-358297, EBI-713279; CC O00505; Q13322-4: GRB10; NbExp=3; IntAct=EBI-358297, EBI-12353035; CC O00505; Q96MH2: HEXIM2; NbExp=3; IntAct=EBI-358297, EBI-5460660; CC O00505; P07910: HNRNPC; NbExp=5; IntAct=EBI-358297, EBI-357966; CC O00505; P42858: HTT; NbExp=11; IntAct=EBI-358297, EBI-466029; CC O00505; Q92993: KAT5; NbExp=3; IntAct=EBI-358297, EBI-399080; CC O00505; Q14974: KPNB1; NbExp=2; IntAct=EBI-358297, EBI-286758; CC O00505; Q8NA19-2: L3MBTL4; NbExp=3; IntAct=EBI-358297, EBI-12778187; CC O00505; P45984: MAPK9; NbExp=3; IntAct=EBI-358297, EBI-713568; CC O00505; Q9NZL9: MAT2B; NbExp=6; IntAct=EBI-358297, EBI-10317491; CC O00505; Q13330: MTA1; NbExp=3; IntAct=EBI-358297, EBI-714236; CC O00505; Q9HAN9: NMNAT1; NbExp=3; IntAct=EBI-358297, EBI-3917542; CC O00505; Q9UKX7: NUP50; NbExp=6; IntAct=EBI-358297, EBI-2371082; CC O00505; Q9BUI4: POLR3C; NbExp=3; IntAct=EBI-358297, EBI-5452779; CC O00505; P43351: RAD52; NbExp=3; IntAct=EBI-358297, EBI-706448; CC O00505; Q96P16: RPRD1A; NbExp=3; IntAct=EBI-358297, EBI-1053506; CC O00505; Q8WWX8: SLC5A11; NbExp=3; IntAct=EBI-358297, EBI-10277669; CC O00505; Q8WWX8-3: SLC5A11; NbExp=3; IntAct=EBI-358297, EBI-12697471; CC O00505; Q96LM6: SPMIP9; NbExp=3; IntAct=EBI-358297, EBI-743976; CC O00505; P0DTL5: TMEM276; NbExp=3; IntAct=EBI-358297, EBI-11997340; CC O00505; Q96KP6: TNIP3; NbExp=3; IntAct=EBI-358297, EBI-2509913; CC O00505; Q9Y5U2: TSSC4; NbExp=4; IntAct=EBI-358297, EBI-717229; CC O00505; Q2YD98: UVSSA; NbExp=3; IntAct=EBI-358297, EBI-11153331; CC O00505; O43167: ZBTB24; NbExp=3; IntAct=EBI-358297, EBI-744471; CC O00505; Q8TBK6: ZCCHC10; NbExp=3; IntAct=EBI-358297, EBI-597063; CC O00505; Q6PEW1: ZCCHC12; NbExp=3; IntAct=EBI-358297, EBI-748373; CC O00505; P36508: ZNF76; NbExp=3; IntAct=EBI-358297, EBI-7254550; CC O00505; Q96H86: ZNF764; NbExp=3; IntAct=EBI-358297, EBI-745775; CC O00505; Q9BRL8; NbExp=3; IntAct=EBI-358297, EBI-10297046; CC O00505; K9N643: ORF4b; Xeno; NbExp=4; IntAct=EBI-358297, EBI-25641007; CC O00505; P03427: PB2; Xeno; NbExp=3; IntAct=EBI-358297, EBI-8430745; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:34564892}. Nucleus CC {ECO:0000269|PubMed:34564892}. CC -!- TISSUE SPECIFICITY: Ubiquitous. Highest levels in heart and skeletal CC muscle. CC -!- DOMAIN: Consists of an N-terminal hydrophilic region, a hydrophobic CC central region composed of 10 repeats, and a short hydrophilic C- CC terminus. The N-terminal hydrophilic region contains the importin beta CC binding domain (IBB domain), which is sufficient for binding importin CC beta and essential for nuclear protein import. CC -!- DOMAIN: The IBB domain is thought to act as an intrasteric CC autoregulatory sequence by interacting with the internal autoinhibitory CC NLS. Binding of KPNB1 probably overlaps the internal NLS and CC contributes to a high affinity for cytoplasmic NLS-containing cargo CC substrates. After dissociation of the importin/substrate complex in the CC nucleus the internal autohibitory NLS contributes to a low affinity for CC nuclear NLS-containing proteins (By similarity). {ECO:0000250}. CC -!- DOMAIN: The major and minor NLS binding sites are mainly involved in CC recognition of simple or bipartite NLS motifs. Structurally located CC within in a helical surface groove they contain several conserved Trp CC and Asn residues of the corresponding third helices (H3) of ARM repeats CC which mainly contribute to binding (By similarity). {ECO:0000250}. CC -!- DISEASE: Spastic paraplegia 88, autosomal dominant (SPG88) CC [MIM:620106]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. SPG88 is characterized CC by onset of symptoms in the first year of life. Most SPG88 patients CC have a pure form of the disorder, although rarely patients may manifest CC additional features, including peripheral neuropathy, speech delay, CC attention deficit hyperactivity disorder, and non-specific brain CC imaging abnormalities. {ECO:0000269|PubMed:34564892, CC ECO:0000269|PubMed:34825409, ECO:0000269|PubMed:34981581}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the importin alpha family. {ECO:0000305}. CC -!- CAUTION: Was termed importin alpha-4. {ECO:0000305|PubMed:9395085}. 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; D89618; BAA20378.1; -; mRNA. DR EMBL; Y12394; CAA73026.1; -; mRNA. DR EMBL; AF034756; AAB87693.1; -; mRNA. DR EMBL; AF005263; AAQ13404.1; -; mRNA. DR EMBL; AK290528; BAF83217.1; -; mRNA. DR EMBL; AK291000; BAF83689.1; -; mRNA. DR EMBL; AL136301; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL135901; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471075; EAX08837.1; -; Genomic_DNA. DR EMBL; BC017355; AAH17355.1; -; mRNA. DR EMBL; BC024202; AAH24202.1; -; mRNA. DR EMBL; BC035090; AAH35090.1; -; mRNA. DR CCDS; CCDS9421.1; -. DR RefSeq; NP_002258.2; NM_002267.3. DR AlphaFoldDB; O00505; -. DR SMR; O00505; -. DR BioGRID; 110037; 244. DR ComplexPortal; CPX-1057; Importin complex, KPNA3 variant. DR CORUM; O00505; -. DR DIP; DIP-27586N; -. DR IntAct; O00505; 114. DR MINT; O00505; -. DR STRING; 9606.ENSP00000261667; -. DR ChEMBL; CHEMBL4523119; -. DR TCDB; 1.I.1.1.3; the nuclear pore complex (npc) family. DR GlyGen; O00505; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O00505; -. DR PhosphoSitePlus; O00505; -. DR SwissPalm; O00505; -. DR BioMuta; KPNA3; -. DR EPD; O00505; -. DR jPOST; O00505; -. DR MassIVE; O00505; -. DR MaxQB; O00505; -. DR PaxDb; 9606-ENSP00000261667; -. DR PeptideAtlas; O00505; -. DR ProteomicsDB; 47946; -. DR Pumba; O00505; -. DR Antibodypedia; 23966; 230 antibodies from 33 providers. DR DNASU; 3839; -. DR Ensembl; ENST00000261667.8; ENSP00000261667.3; ENSG00000102753.10. DR GeneID; 3839; -. DR KEGG; hsa:3839; -. DR MANE-Select; ENST00000261667.8; ENSP00000261667.3; NM_002267.4; NP_002258.2. DR UCSC; uc001vdj.2; human. DR AGR; HGNC:6396; -. DR CTD; 3839; -. DR DisGeNET; 3839; -. DR GeneCards; KPNA3; -. DR HGNC; HGNC:6396; KPNA3. DR HPA; ENSG00000102753; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; KPNA3; -. DR MIM; 601892; gene. DR MIM; 620106; phenotype. DR neXtProt; NX_O00505; -. DR OpenTargets; ENSG00000102753; -. DR Orphanet; 171612; Autosomal dominant spastic paraplegia type 37. DR PharmGKB; PA30187; -. DR VEuPathDB; HostDB:ENSG00000102753; -. DR eggNOG; KOG0166; Eukaryota. DR GeneTree; ENSGT01050000244891; -. DR HOGENOM; CLU_018084_6_1_1; -. DR InParanoid; O00505; -. DR OMA; GGNEHIQ; -. DR OrthoDB; 916229at2759; -. DR PhylomeDB; O00505; -. DR TreeFam; TF101178; -. DR PathwayCommons; O00505; -. DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism. DR Reactome; R-HSA-168276; NS1 Mediated Effects on Host Pathways. DR SignaLink; O00505; -. DR SIGNOR; O00505; -. DR BioGRID-ORCS; 3839; 15 hits in 1160 CRISPR screens. DR ChiTaRS; KPNA3; human. DR GeneWiki; KPNA3; -. DR GenomeRNAi; 3839; -. DR Pharos; O00505; Tbio. DR PRO; PR:O00505; -. DR Proteomes; UP000005640; Chromosome 13. DR RNAct; O00505; Protein. DR Bgee; ENSG00000102753; Expressed in biceps brachii and 212 other cell types or tissues. DR ExpressionAtlas; O00505; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0043657; C:host cell; IEA:GOC. DR GO; GO:0042564; C:NLS-dependent protein nuclear import complex; IPI:ComplexPortal. DR GO; GO:0005643; C:nuclear pore; TAS:ProtInc. DR GO; GO:0005654; C:nucleoplasm; IBA:GO_Central. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0061608; F:nuclear import signal receptor activity; IBA:GO_Central. DR GO; GO:0008139; F:nuclear localization sequence binding; IBA:GO_Central. DR GO; GO:0006607; P:NLS-bearing protein import into nucleus; IBA:GO_Central. DR GO; GO:0006606; P:protein import into nucleus; ISS:ComplexPortal. DR GO; GO:0065003; P:protein-containing complex assembly; TAS:ProtInc. DR GO; GO:0046718; P:viral entry into host cell; IEA:UniProtKB-KW. DR GO; GO:0075732; P:viral penetration into host nucleus; IEA:UniProtKB-KW. DR Gene3D; 1.20.5.690; Importin-alpha, importin-beta-binding domain; 1. DR Gene3D; 1.25.10.10; Leucine-rich Repeat Variant; 1. DR InterPro; IPR011989; ARM-like. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR032413; Arm_3. DR InterPro; IPR000225; Armadillo. DR InterPro; IPR002652; Importin-a_IBB. DR InterPro; IPR036975; Importin-a_IBB_sf. DR InterPro; IPR024931; Importin_alpha. DR PANTHER; PTHR23316; IMPORTIN ALPHA; 1. DR PANTHER; PTHR23316:SF6; IMPORTIN SUBUNIT ALPHA-4; 1. DR Pfam; PF00514; Arm; 8. DR Pfam; PF16186; Arm_3; 1. DR Pfam; PF01749; IBB; 1. DR PIRSF; PIRSF005673; Importin_alpha; 1. DR SMART; SM00185; ARM; 8. DR SUPFAM; SSF48371; ARM repeat; 1. DR PROSITE; PS50176; ARM_REPEAT; 3. DR PROSITE; PS51214; IBB; 1. DR Genevisible; O00505; HS. PE 1: Evidence at protein level; KW Acetylation; Cytoplasm; Disease variant; Hereditary spastic paraplegia; KW Host-virus interaction; Neurodegeneration; Nucleus; Phosphoprotein; KW Protein transport; Reference proteome; Repeat; Transport; KW Viral penetration into host nucleus; Virus entry into host cell. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19413330" FT CHAIN 2..521 FT /note="Importin subunit alpha-4" FT /id="PRO_0000120724" FT DOMAIN 2..58 FT /note="IBB" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00561" FT REPEAT 66..106 FT /note="ARM 1; truncated" FT REPEAT 107..149 FT /note="ARM 2" FT REPEAT 150..194 FT /note="ARM 3" FT REPEAT 195..233 FT /note="ARM 4" FT REPEAT 234..278 FT /note="ARM 5" FT REPEAT 279..318 FT /note="ARM 6" FT REPEAT 319..360 FT /note="ARM 7" FT REPEAT 361..400 FT /note="ARM 8" FT REPEAT 401..443 FT /note="ARM 9" FT REPEAT 447..485 FT /note="ARM 10; atypical" FT REGION 1..29 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 137..229 FT /note="NLS binding site (major)" FT /evidence="ECO:0000250" FT REGION 306..394 FT /note="NLS binding site (minor)" FT /evidence="ECO:0000250" FT MOTIF 43..52 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250" FT COMPBIAS 9..29 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:19413330" FT MOD_RES 56 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 60 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:18318008, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 484 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:24275569" FT VARIANT 291 FT /note="P -> S (in dbSNP:rs1043015)" FT /id="VAR_014454" FT VARIANT 315 FT /note="T -> I (in SPG88; decreased interaction with RCC1 FT and DDX21; no effect on interaction with NCBP1 and NCBP2)" FT /evidence="ECO:0000269|PubMed:34564892, FT ECO:0000269|PubMed:34981581" FT /id="VAR_087813" FT VARIANT 328 FT /note="L -> M (in SPG88; decreased interaction with RCC1 FT and DDX21; no effect on interaction with NCBP1 and NCBP2)" FT /evidence="ECO:0000269|PubMed:34564892" FT /id="VAR_087814" FT VARIANT 328 FT /note="L -> P (in SPG88; loss of interaction with DDX21 and FT NCBP1; severely decreased interaction with RCC1 and NCBP2; FT compared to the wild type, the mutant shows increased FT cytoplasmic levels)" FT /evidence="ECO:0000269|PubMed:34564892, FT ECO:0000269|PubMed:34825409" FT /id="VAR_087815" FT VARIANT 334 FT /note="L -> R (in SPG88; decreased interaction with RCC1, FT DDX21, NCBP1 and NCBP2; compared to the wild type, the FT mutant shows increased cytoplasmic levels)" FT /evidence="ECO:0000269|PubMed:34564892" FT /id="VAR_087816" FT VARIANT 350 FT /note="L -> P (in SPG88; loss of interaction with RCC1, FT DDX21, NCBP1 and NCBP2)" FT /evidence="ECO:0000269|PubMed:34564892" FT /id="VAR_087817" FT VARIANT 415 FT /note="P -> L (in SPG88; loss of interaction with RCC1; FT severely decreased interaction with DDX21 and NCBP1; no FT effect on interaction with NCBP2)" FT /evidence="ECO:0000269|PubMed:34564892" FT /id="VAR_087818" FT CONFLICT 34 FT /note="V -> M (in Ref. 2; CAA73026)" FT /evidence="ECO:0000305" FT CONFLICT 103 FT /note="R -> Q (in Ref. 1; BAA20378)" FT /evidence="ECO:0000305" FT CONFLICT 152..153 FT /note="AV -> DI (in Ref. 8; AAH35090)" FT /evidence="ECO:0000305" FT CONFLICT 154 FT /note="V -> G (in Ref. 3; AAB87693)" FT /evidence="ECO:0000305" FT CONFLICT 236 FT /note="P -> T (in Ref. 3; AAB87693)" FT /evidence="ECO:0000305" FT CONFLICT 237 FT /note="M -> L (in Ref. 2; CAA73026)" FT /evidence="ECO:0000305" FT CONFLICT 256 FT /note="I -> V (in Ref. 2; CAA73026)" FT /evidence="ECO:0000305" FT CONFLICT 259 FT /note="L -> V (in Ref. 2; CAA73026)" FT /evidence="ECO:0000305" FT CONFLICT 332 FT /note="P -> Q (in Ref. 8; AAH35090)" FT /evidence="ECO:0000305" FT CONFLICT 411 FT /note="N -> D (in Ref. 8; AAH35090)" FT /evidence="ECO:0000305" SQ SEQUENCE 521 AA; 57811 MW; C4FF132C3F346B7F CRC64; MAENPSLENH RIKSFKNKGR DVETMRRHRN EVTVELRKNK RDEHLLKKRN VPQEESLEDS DVDADFKAQN VTLEAILQNA TSDNPVVQLS AVQAARKLLS SDRNPPIDDL IKSGILPILV KCLERDDNPS LQFEAAWALT NIASGTSAQT QAVVQSNAVP LFLRLLRSPH QNVCEQAVWA LGNIIGDGPQ CRDYVISLGV VKPLLSFISP SIPITFLRNV TWVIVNLCRN KDPPPPMETV QEILPALCVL IYHTDINILV DTVWALSYLT DGGNEQIQMV IDSGVVPFLV PLLSHQEVKV QTAALRAVGN IVTGTDEQTQ VVLNCDVLSH FPNLLSHPKE KINKEAVWFL SNITAGNQQQ VQAVIDAGLI PMIIHQLAKG DFGTQKEAAW AISNLTISGR KDQVEYLVQQ NVIPPFCNLL SVKDSQVVQV VLDGLKNILI MAGDEASTIA EIIEECGGLE KIEVLQQHEN EDIYKLAFEI IDQYFSGDDI DEDPCLIPEA TQGGTYNFDP TANLQTKEFN F //