ID A9Y695_9HIV1 Unreviewed; 86 AA. AC A9Y695; DT 05-FEB-2008, integrated into UniProtKB/TrEMBL. DT 05-FEB-2008, sequence version 1. DT 20-JUN-2018, entry version 46. DE RecName: Full=Protein Tat {ECO:0000256|HAMAP-Rule:MF_04079, ECO:0000256|RuleBase:RU003311, ECO:0000256|SAAS:SAAS00396010}; DE AltName: Full=Transactivating regulatory protein {ECO:0000256|HAMAP-Rule:MF_04079}; GN Name=tat {ECO:0000256|HAMAP-Rule:MF_04079, GN ECO:0000313|EMBL:ABW86719.1}; OS Human immunodeficiency virus 1. OC Viruses; Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus. OX NCBI_TaxID=11676 {ECO:0000313|EMBL:ABW86719.1, ECO:0000313|Proteomes:UP000102958}; OH NCBI_TaxID=9606; Homo sapiens (Human). RN [1] {ECO:0000313|EMBL:ABW86719.1, ECO:0000313|Proteomes:UP000102958} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=ML1974 {ECO:0000313|EMBL:ABW86719.1}; RX PubMed=18544023; DOI=10.1089/aid.2007.0200; RA Land A.M., Ball T.B., Luo M., Rutherford J., Sarna C., Wachihi C., RA Kimani J., Plummer F.A.; RT "Full-length HIV type 1 proviral sequencing of 10 highly exposed women RT from Nairobi, Kenya reveals a high proportion of intersubtype RT recombinants."; RL AIDS Res. Hum. Retroviruses 24:865-872(2008). CC -!- FUNCTION: Extracellular circulating Tat can be endocytosed by CC surrounding uninfected cells via the binding to several surface CC receptors such as CD26, CXCR4, heparan sulfate proteoglycans CC (HSPG) or LDLR. Neurons are rarely infected, but they internalize CC Tat via their LDLR. Through its interaction with nuclear HATs, Tat CC is potentially able to control the acetylation-dependent cellular CC gene expression. Modulates the expression of many cellular genes CC involved in cell survival, proliferation or in coding for CC cytokines or cytokine receptors. Tat plays a role in T-cell and CC neurons apoptosis. Tat induced neurotoxicity and apoptosis CC probably contribute to neuroAIDS. Circulating Tat also acts as a CC chemokine-like and/or growth factor-like molecule that binds to CC specific receptors on the surface of the cells, affecting many CC cellular pathways. In the vascular system, Tat binds to CC ITGAV/ITGB3 and ITGA5/ITGB1 integrins dimers at the surface of CC endothelial cells and competes with bFGF for heparin-binding CC sites, leading to an excess of soluble bFGF. {ECO:0000256|HAMAP- CC Rule:MF_04079}. CC -!- FUNCTION: Nuclear transcriptional activator of viral gene CC expression, that is essential for viral transcription from the LTR CC promoter and replication. Acts as a sequence-specific molecular CC adapter, directing components of the cellular transcription CC machinery to the viral RNA to promote processive transcription CC elongation by the RNA polymerase II (RNA pol II) complex, thereby CC increasing the level of full-length transcripts. In the absence of CC Tat, the RNA Pol II generates short or non-processive transcripts CC that terminate at approximately 60 bp from the initiation site. CC Tat associates with the CCNT1/cyclin-T1 component of the P-TEFb CC complex (CDK9 and CCNT1), which promotes RNA chain elongation. CC This binding increases Tat's affinity for a hairpin structure at CC the 5'-end of all nascent viral mRNAs referred to as the CC transactivation responsive RNA element (TAR RNA) and allows Tat/P- CC TEFb complex to bind cooperatively to TAR RNA. The CDK9 component CC of P-TEFb and other Tat-activated kinases hyperphosphorylate the CC C-terminus of RNA Pol II that becomes stabilized and much more CC processive. Other factors such as HTATSF1/Tat-SF1, SUPT5H/SPT5, CC and HTATIP2 are also important for Tat's function. Besides its CC effect on RNA Pol II processivity, Tat induces chromatin CC remodeling of proviral genes by recruiting the histone CC acetyltransferases (HATs) CREBBP, EP300 and PCAF to the chromatin. CC This also contributes to the increase in proviral transcription CC rate, especially when the provirus integrates in transcriptionally CC silent region of the host genome. To ensure maximal activation of CC the LTR, Tat mediates nuclear translocation of NF-kappa-B by CC interacting with host RELA. Through its interaction with host TBP, CC Tat may also modulate transcription initiation. Tat can reactivate CC a latently infected cell by penetrating in it and transactivating CC its LTR promoter. In the cytoplasm, Tat is thought to act as a CC translational activator of HIV-1 mRNAs. {ECO:0000256|HAMAP- CC Rule:MF_04079}. CC -!- SUBUNIT: Interacts with host CCNT1. Associates with the P-TEFb CC complex composed at least of Tat, P-TEFb (CDK9 and CCNT1), TAR CC RNA, RNA Pol II. Recruits the HATs CREBBP, TAF1/TFIID, EP300, PCAF CC and GCN5L2. Interacts with host KAT5/Tip60; this interaction CC targets the latter to degradation. Interacts with the host CC deacetylase SIRT1. Interacts with host capping enzyme RNGTT; this CC interaction stimulates RNGTT. Binds to host KDR, and to the host CC integrins ITGAV/ITGB3 and ITGA5/ITGB1. Interacts with host CC KPNB1/importin beta-1 without previous binding to KPNA1/importin CC alpha-1. Interacts with EIF2AK2. Interacts with host nucleosome CC assembly protein NAP1L1; this interaction may be required for the CC transport of Tat within the nucleus, since the two proteins CC interact at the nuclear rim. Interacts with host C1QBP/SF2P32; CC this interaction involves lysine-acetylated Tat. Interacts with CC the host chemokine receptors CCR2, CCR3 and CXCR4. Interacts with CC host DPP4/CD26; this interaction may trigger an anti-proliferative CC effect. Interacts with host LDLR. Interacts with the host CC extracellular matrix metalloproteinase MMP1. Interacts with host CC PRMT6; this interaction mediates Tat's methylation. Interacts CC with, and is ubiquitinated by MDM2/Hdm2. Interacts with host PSMC3 CC and HTATIP2. Interacts with STAB1; this interaction may overcome CC SATB1-mediated repression of IL2 and IL2RA (interleukin) in T CC cells by binding to the same domain than HDAC1. Interacts (when CC acetylated) with human CDK13, thereby increasing HIV-1 mRNA CC splicing and promoting the production of the doubly spliced HIV-1 CC protein Nef.Interacts with host TBP; this interaction modulates CC the activity of transcriptional pre-initiation complex. Interacts CC with host RELA. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- SUBCELLULAR LOCATION: Host nucleus, host nucleolus CC {ECO:0000256|HAMAP-Rule:MF_04079}. Host cytoplasm CC {ECO:0000256|HAMAP-Rule:MF_04079}. Secreted {ECO:0000256|HAMAP- CC Rule:MF_04079}. Note=Probably localizes to both nuclear and CC nucleolar compartments. Nuclear localization is mediated through CC the interaction of the nuclear localization signal with importin CC KPNB1. Secretion occurs through a Golgi-independent pathway. Tat CC is released from infected cells to the extracellular space where CC it remains associated to the cell membrane, or is secreted into CC the cerebrospinal fluid and sera. Extracellular Tat can be CC endocytosed by surrounding uninfected cells via binding to several CC receptors depending on the cell type. {ECO:0000256|HAMAP- CC Rule:MF_04079}. CC -!- DOMAIN: The Arg-rich RNA-binding region binds the TAR RNA. This CC region also mediates the nuclear localization through direct CC binding to KPNB1 and is involved in Tat's transfer across cell CC membranes (protein transduction). The same region is required for CC the interaction with EP300, PCAF, EIF2AK2 and KDR. CC {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- DOMAIN: The Cys-rich region may bind 2 zinc ions. This region is CC involved in binding to KAT5. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- DOMAIN: The cell attachment site mediates the interaction with CC ITGAV/ITGB3 and ITGA5/ITGB1 integrins, leading to vascular cell CC migration and invasion. This interaction also provides endothelial CC cells with the adhesion signal they require to grow in response to CC mitogens. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- DOMAIN: The transactivation domain mediates the interaction with CC CCNT1, GCN5L2, and MDM2. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- PTM: Acetylation by EP300, CREBBP, GCN5L2/GCN5 and PCAF regulates CC the transactivation activity of Tat. EP300-mediated acetylation of CC Lys-50 promotes dissociation of Tat from the TAR RNA through the CC competitive binding to PCAF's bromodomain. In addition, the non- CC acetylated Tat's N-terminus can also interact with PCAF. PCAF- CC mediated acetylation of Lys-28 enhances Tat's binding to CCNT1. CC Lys-50 is deacetylated by SIRT1. {ECO:0000256|HAMAP- CC Rule:MF_04079}. CC -!- PTM: Asymmetrical arginine methylation by host PRMT6 seems to CC diminish the transactivation capacity of Tat and affects the CC interaction with host CCNT1. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- PTM: Phosphorylated by EIF2AK2 on serine and threonine residues CC adjacent to the basic region important for TAR RNA binding and CC function. Phosphorylation of Tat by EIF2AK2 is dependent on the CC prior activation of EIF2AK2 by dsRNA. {ECO:0000256|HAMAP- CC Rule:MF_04079}. CC -!- PTM: Polyubiquitination by host MDM2 does not target Tat to CC degradation, but activates its transactivation function and CC fosters interaction with CCNT1 and TAR RNA. {ECO:0000256|HAMAP- CC Rule:MF_04079}. CC -!- MISCELLANEOUS: HIV-1 lineages are divided in three main groups, M CC (for Major), O (for Outlier), and N (for New, or Non-M, Non-O). CC The vast majority of strains found worldwide belong to the group CC M. Group O seems to be endemic to and largely confined to Cameroon CC and neighboring countries in West Central Africa, where these CC viruses represent a small minority of HIV-1 strains. The group N CC is represented by a limited number of isolates from Cameroonian CC persons. The group M is further subdivided in 9 clades or subtypes CC (A to D, F to H, J and K). {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- SIMILARITY: Belongs to the lentiviruses Tat family. CC {ECO:0000256|HAMAP-Rule:MF_04079, ECO:0000256|RuleBase:RU003311, CC ECO:0000256|SAAS:SAAS00581731}. 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; EU110090; ABW86719.1; -; Genomic_DNA. DR ProteinModelPortal; A9Y695; -. DR Proteomes; UP000102958; Genome. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0044196; C:host cell nucleolus; IEA:UniProtKB-SubCell. DR GO; GO:0042805; F:actinin binding; IEA:UniProtKB-UniRule. DR GO; GO:0030332; F:cyclin binding; IEA:UniProtKB-UniRule. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-UniRule. DR GO; GO:0019904; F:protein domain specific binding; IEA:UniProtKB-UniRule. DR GO; GO:0001070; F:RNA binding transcription regulator activity; IEA:UniProtKB-UniRule. DR GO; GO:1990970; F:trans-activation response element binding; IEA:UniProtKB-UniRule. DR GO; GO:0039525; P:modulation by virus of host chromatin organization; IEA:UniProtKB-UniRule. DR GO; GO:0039586; P:modulation by virus of host PP1 activity; IEA:UniProtKB-UniRule. DR GO; GO:0010801; P:negative regulation of peptidyl-threonine phosphorylation; IEA:UniProtKB-UniRule. DR GO; GO:0032968; P:positive regulation of transcription elongation from RNA polymerase II promoter; IEA:UniProtKB-UniRule. DR GO; GO:0050434; P:positive regulation of viral transcription; IEA:UniProtKB-UniRule. DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-UniRule. DR GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-UniRule. DR Gene3D; 4.10.20.10; -; 1. DR HAMAP; MF_04079; HIV_TAT; 1. DR InterPro; IPR001831; IV_Tat. DR InterPro; IPR036963; Tat_dom_sf. DR Pfam; PF00539; Tat; 1. DR PRINTS; PR00055; HIVTATDOMAIN. PE 3: Inferred from homology; KW Acetylation {ECO:0000256|HAMAP-Rule:MF_04079}; KW Activator {ECO:0000256|HAMAP-Rule:MF_04079, KW ECO:0000256|RuleBase:RU003311, ECO:0000256|SAAS:SAAS00111091}; KW Apoptosis {ECO:0000256|HAMAP-Rule:MF_04079}; KW Complete proteome {ECO:0000313|Proteomes:UP000102958}; KW Host cytoplasm {ECO:0000256|HAMAP-Rule:MF_04079}; KW Host nucleus {ECO:0000256|HAMAP-Rule:MF_04079, KW ECO:0000256|RuleBase:RU003311, ECO:0000256|SAAS:SAAS00473431}; KW Host-virus interaction {ECO:0000256|HAMAP-Rule:MF_04079, KW ECO:0000256|SAAS:SAAS00111166}; KW Inhibition of host innate immune response by virus {ECO:0000256|HAMAP- KW Rule:MF_04079}; KW Inhibition of host interferon signaling pathway by virus KW {ECO:0000256|HAMAP-Rule:MF_04079}; KW Isopeptide bond {ECO:0000256|HAMAP-Rule:MF_04079}; KW Metal-binding {ECO:0000256|HAMAP-Rule:MF_04079}; KW Methylation {ECO:0000256|HAMAP-Rule:MF_04079}; KW Modulation of host chromatin by virus {ECO:0000256|HAMAP- KW Rule:MF_04079}; KW Modulation of host PP1 activity by virus {ECO:0000256|HAMAP- KW Rule:MF_04079}; Phosphoprotein {ECO:0000256|HAMAP-Rule:MF_04079}; KW RNA-binding {ECO:0000256|HAMAP-Rule:MF_04079, KW ECO:0000256|RuleBase:RU003311, ECO:0000256|SAAS:SAAS00111359}; KW Secreted {ECO:0000256|HAMAP-Rule:MF_04079}; KW Transcription {ECO:0000256|HAMAP-Rule:MF_04079, KW ECO:0000256|RuleBase:RU003311, ECO:0000256|SAAS:SAAS00111391}; KW Transcription regulation {ECO:0000256|HAMAP-Rule:MF_04079, KW ECO:0000256|RuleBase:RU003311, ECO:0000256|SAAS:SAAS00111074}; KW Ubl conjugation {ECO:0000256|HAMAP-Rule:MF_04079}; KW Viral immunoevasion {ECO:0000256|HAMAP-Rule:MF_04079}; KW Zinc {ECO:0000256|HAMAP-Rule:MF_04079}. FT REGION 1 48 Transactivation. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT REGION 1 24 Interaction with human CREBBP. FT {ECO:0000256|HAMAP-Rule:MF_04079}. FT REGION 22 37 Cysteine-rich. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT REGION 38 48 Core. {ECO:0000256|HAMAP-Rule:MF_04079}. FT REGION 49 86 Interaction with the host capping enzyme FT RNGTT. {ECO:0000256|HAMAP-Rule:MF_04079}. FT MOTIF 49 57 Nuclear localization signal, RNA-binding FT (TAR), and protein transduction. FT {ECO:0000256|HAMAP-Rule:MF_04079}. FT MOTIF 78 80 Cell attachment site. {ECO:0000256|HAMAP- FT Rule:MF_04079}. FT METAL 22 22 Zinc 1. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT METAL 25 25 Zinc 2. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT METAL 27 27 Zinc 2. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT METAL 30 30 Zinc 2. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT METAL 33 33 Zinc 1; via pros nitrogen. FT {ECO:0000256|HAMAP-Rule:MF_04079}. FT METAL 34 34 Zinc 1. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT METAL 37 37 Zinc 1. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT SITE 11 11 Essential for Tat translocation through FT the endosomal membrane. FT {ECO:0000256|HAMAP-Rule:MF_04079}. FT MOD_RES 28 28 N6-acetyllysine; by host PCAF. FT {ECO:0000256|HAMAP-Rule:MF_04079}. FT MOD_RES 50 50 N6-acetyllysine; by host EP300 and FT GCN5L2. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT MOD_RES 51 51 N6-acetyllysine; by host EP300 and FT GCN5L2. {ECO:0000256|HAMAP-Rule: FT MF_04079}. FT MOD_RES 52 52 Asymmetric dimethylarginine; by host FT PRMT6. {ECO:0000256|HAMAP-Rule:MF_04079}. FT MOD_RES 53 53 Asymmetric dimethylarginine; by host FT PRMT6. {ECO:0000256|HAMAP-Rule:MF_04079}. FT CROSSLNK 71 71 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000256|HAMAP-Rule:MF_04079}. SQ SEQUENCE 86 AA; 9837 MW; E739BC496DEAEB73 CRC64; MDPVDPRLEP WNHPGSQPRT PCNQCYCKKC CYHCQHCFIT KGLGISYGRK KRRQRRSAPH GDQSHQDPIP KQPSSQPRGD PTGPKE //