UniProt Accession

 DDX3X_HUMAN; O00571; A8K538; B4E3E8; O15536 

Genbank Protein ID

 U50553; AF061337; AF000983; AF000982; AK291153; AK304689; AL391647; Z93015; CH471141; CH471141; CH471141; CH471141; BC011819 

Genbank Nucleotide ID

 AAB95637.1; AAC34298.1; AAC51830.1; AAC51829.1; BAF83842.1; BAG65460.1; CAI41416.1; EAW59402.1; EAW59403.1; EAW59404.1; EAW59405.1; AAH11819.1 

Protein Name

 ATP-dependent RNA helicase DDX3X 

Protein Synonyms/Alias

 DEAD box protein 3, X-chromosomal; DEAD box, X isoform; Helicase-like protein 2; HLP2 

Gene Name

 DDX3X 

Gene Synonyms/Alias

 DBX; DDX3 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
55	ATKGFYDKDSSGWSS	ubiquitination	[1, 2, 3]
81	SRSDSRGKSSFFSDR	ubiquitination	[2]
118	GDRSGFGKFERGGNS	acetylation	[4]
118	GDRSGFGKFERGGNS	ubiquitination	[2, 5, 6]
208	TRPTPVQKHAIPIIK	ubiquitination	[1, 3]
215	KHAIPIIKEKRDLMA	ubiquitination	[2]
217	AIPIIKEKRDLMACA	ubiquitination	[2]
264	NGRYGRRKQYPISLV	ubiquitination	[1, 3, 7]
335	VDMMERGKIGLDFCK	ubiquitination	[5]
418	TSENITQKVVWVEES	ubiquitination	[2]
427	VWVEESDKRSFLLDL	ubiquitination	[2]
511	GLDISNVKHVINFDL	acetylation	[8]
511	GLDISNVKHVINFDL	ubiquitination	[2, 5, 6, 9]
554	ERNINITKDLLDLLV	ubiquitination	[2, 5, 6, 10, 11]

Reference

 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [3] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [4] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [5] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [6] Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.
 Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.
 Nature. 2013 Apr 18;496(7445):372-6. [PMID: 23503661]
 [7] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [8] Monoclonal antibody cocktail as an enrichment tool for acetylome analysis.
 Shaw PG, Chaerkady R, Zhang Z, Davidson NE, Pandey A.
 Anal Chem. 2011 May 15;83(10):3623-6. [PMID: 21466224]
 [9] Global identification of modular cullin-RING ligase substrates.
 Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ.
 Cell. 2011 Oct 14;147(2):459-74. [PMID: 21963094]
 [10] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]
 [11] Proteome-wide identification of ubiquitylation sites by conjugation of engineered lysine-less ubiquitin.
 Oshikawa K, Matsumoto M, Oyamada K, Nakayama KI.
 J Proteome Res. 2012 Feb 3;11(2):796-807. [PMID: 22053931] 

Functional Description

 Multifunctional ATP-dependent RNA helicase. The ATPase activity can be stimulated by various ribo- and deoxynucleic acids indicative for a relaxed substrate specificity. In vitro can unwind partially double stranded DNA with a preference for 5'- single stranded DNA overhangs. Is involved in several steps of gene expression, such as transcription, mRNA maturation, mRNA export and translation. However, the exact mechanisms are not known and some functions may be specific for a subset of mRNAs. Involved in transcriptional regulation. Can enhance transcription from the CDKN1A/WAF1 promoter in a SP1-dependent manner. Found associated with the E-cadherin promoter and can down-regulate transcription from the promoter. Involved in regulation of translation initiation. Proposed to be involved in positive regulation of translation such as of cyclin E1/CCNE1 mRNA and specifically of mRNAs containing complex secondary structures in their 5'UTRs; these functions seem to require RNA helicase activity. Specifically promotes translation of a subset of viral and cellular mRNAs carrying a 5'proximal stem-loop structure in their 5'UTRs and cooperates with the eIF4F complex. Proposed to act prior to 43S ribosomal scanning and to locally destabilize these RNA structures to allow recognition of the mRNA cap or loading onto the 40S subunit. After association with 40S ribosomal subunits seems to be involved in the functional assembly of 80S ribosomes; the function seems to cover translation of mRNAs with structured and non-structured 5'UTRs and is independent of RNA helicase activity. Also proposed to inhibit cap-dependent translation by competetive interaction with EIF4E which can block the EIF4E:EIF4G complex formation. Proposed to be involved in stress response and stress granule assembly; the function is independent of RNA helicase activity and seems to involve association with EIF4E. May be involved in nuclear export of specific mRNAs but not in bulk mRNA export via interactions with XPO1 and NXF1. Also associates with polyadenylated mRNAs independently of NXF1. Associates with spliced mRNAs in an exon junction complex (EJC)-dependent manner and seems not to be directly involved in splicing. May be involved in nuclear mRNA export by association with DDX5 and regulating its nuclear location. Involved in innate immune signaling promoting the production of type I interferon (IFN-alpha and IFN-beta); proposed to act as viral RNA sensor, signaling intermediate and transcriptional coactivator. Involved in TBK1 and IKBKE-dependent IRF3 activation leading to IFN-beta induction. Also found associated with IFN-beta promoters; the function is independent of IRF3. Can bind to viral RNAs and via association with MAVS/IPS1 and DDX58/RIG-I is thought to induce signaling in early stages of infection. Involved in regulation of apoptosis. May be required for activation of the intrinsic but inhibit activation of the extrinsic apoptotic pathway. Acts as an antiapoptotic protein through association with GSK3A/B and BIRC2 in an apoptosis antagonizing signaling complex; activation of death receptors promotes caspase-dependent cleavage of BIRC2 and DDX3X and relieves the inhibition. May be involved in mitotic chromosome segregation. Appears to be a prime target for viral manipulations. Hepatitis B virus (HBV) polymerase and possibly vaccinia virus (VACV) protein K7 inhibit IFN-beta induction probably by dissociating DDX3X from TBK1 or IKBKE. Is involved in hepatitis C virus (HCV) replication; the function may involve the association with HCV core protein. HCV core protein inhibits the IPS1- dependent function in viral RNA sensing and may switch the function from a INF-beta inducing to a HCV replication mode. Involved in HIV-1 replication. Acts as a cofactor for XPO1- mediated nuclear export of incompletely spliced HIV-1 Rev RNAs. 

Sequence Annotation

 DOMAIN 211 403 Helicase ATP-binding.
 DOMAIN 414 575 Helicase C-terminal.
 NP_BIND 200 207 ATP.
 NP_BIND 224 231 ATP.
 REGION 2 139 Required for TBK1 and IKBKE-depenedent
 REGION 2 100 Interaction with EIF4E.
 REGION 81 90 Required for interaction with VACV
 REGION 100 662 Interaction with GSK3B.
 REGION 250 259 Involved in stimulation of ATPase
 REGION 260 517 Necessary for interaction with XPO1.
 MOTIF 180 208 Q motif.
 MOTIF 347 350 DEAD box.
 MOD_RES 2 2 N-acetylserine.
 MOD_RES 69 69 Phosphotyrosine.
 MOD_RES 74 74 Phosphoserine.
 MOD_RES 76 76 Phosphoserine.
 MOD_RES 78 78 Phosphoserine.
 MOD_RES 104 104 Phosphotyrosine.
 MOD_RES 118 118 N6-acetyllysine.
 MOD_RES 125 125 Phosphoserine.
 MOD_RES 131 131 Phosphoserine.
 MOD_RES 283 283 Phosphotyrosine (By similarity).
 MOD_RES 343 343 Phosphotyrosine.
 MOD_RES 466 466 Phosphotyrosine (By similarity).
 MOD_RES 590 590 Phosphoserine.
 MOD_RES 594 594 Phosphoserine.
 MOD_RES 612 612 Phosphoserine.  

Keyword

 3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding; Chromosome partition; Complete proteome; Cytoplasm; Direct protein sequencing; DNA-binding; Helicase; Host-virus interaction; Hydrolase; Immunity; Innate immunity; Membrane; Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Ribosome biogenesis; RNA-binding; Transcription; Transcription regulation; Translation regulation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 662 AA 

Protein Sequence

Gene Ontology

 GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB.
 GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
 GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
 GO:0005634; C:nucleus; IDA:UniProtKB.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004003; F:ATP-dependent DNA helicase activity; IDA:UniProtKB.
 GO:0004004; F:ATP-dependent RNA helicase activity; IDA:UniProtKB.
 GO:0003677; F:DNA binding; IDA:UniProtKB.
 GO:0008190; F:eukaryotic initiation factor 4E binding; IDA:UniProtKB.
 GO:0048027; F:mRNA 5'-UTR binding; IDA:UniProtKB.
 GO:0008143; F:poly(A) RNA binding; IDA:UniProtKB.
 GO:0043024; F:ribosomal small subunit binding; IDA:UniProtKB.
 GO:0035613; F:RNA stem-loop binding; IDA:UniProtKB.
 GO:0008134; F:transcription factor binding; IDA:UniProtKB.
 GO:0071243; P:cellular response to arsenic-containing substance; IDA:UniProtKB.
 GO:0071470; P:cellular response to osmotic stress; IDA:UniProtKB.
 GO:0007059; P:chromosome segregation; IMP:UniProtKB.
 GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IMP:UniProtKB.
 GO:0045087; P:innate immune response; IMP:UniProtKB.
 GO:0007243; P:intracellular protein kinase cascade; IDA:UniProtKB.
 GO:0097193; P:intrinsic apoptotic signaling pathway; IMP:UniProtKB.
 GO:0042256; P:mature ribosome assembly; IMP:UniProtKB.
 GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
 GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
 GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:UniProtKB.
 GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
 GO:0031333; P:negative regulation of protein complex assembly; IDA:UniProtKB.
 GO:0017148; P:negative regulation of translation; IMP:UniProtKB.
 GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
 GO:0030307; P:positive regulation of cell growth; IMP:UniProtKB.
 GO:0071651; P:positive regulation of chemokine (C-C motif) ligand 5 production; TAS:UniProtKB.
 GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:UniProtKB.
 GO:1900087; P:positive regulation of G1/S transition of mitotic cell cycle; IMP:UniProtKB.
 GO:0032728; P:positive regulation of interferon-beta production; TAS:UniProtKB.
 GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
 GO:0045948; P:positive regulation of translational initiation; IMP:UniProtKB.
 GO:0009615; P:response to virus; IDA:UniProtKB.
 GO:0010501; P:RNA secondary structure unwinding; IDA:UniProtKB.
 GO:0034063; P:stress granule assembly; IDA:UniProtKB.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0019048; P:virus-host interaction; IEA:UniProtKB-KW. 

Interpro

 IPR011545; DNA/RNA_helicase_DEAD/DEAH_N.
 IPR014001; Helicase_ATP-bd.
 IPR001650; Helicase_C.
 IPR027417; P-loop_NTPase.
 IPR000629; RNA-helicase_DEAD-box_CS.
 IPR014014; RNA_helicase_DEAD_Q_motif. 

Pfam

 PF00270; DEAD
 PF00271; Helicase_C 

SMART

 SM00487; DEXDc
 SM00490; HELICc 

PROSITE

 PS00039; DEAD_ATP_HELICASE
 PS51192; HELICASE_ATP_BIND_1
 PS51194; HELICASE_CTER
 PS51195; Q_MOTIF 

PRINTS