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Cantrelle FX, Loyens A, Trivelli X, Reimann O, Despres C, Gandhi NS, Hackenberger CPR, Landrieu I, Smet-Nocca C. Phosphorylation and O-GlcNAcylation of the PHF-1 Epitope of Tau Protein Induce Local Conformational Changes of the C-Terminus and Modulate Tau Self-Assembly Into Fibrillar Aggregates. Frontiers in molecular neuroscience 2021 14 34220449
Abstract:
Phosphorylation of the neuronal microtubule-associated Tau protein plays a critical role in the aggregation process leading to the formation of insoluble intraneuronal fibrils within Alzheimer's disease (AD) brains. In recent years, other posttranslational modifications (PTMs) have been highlighted in the regulation of Tau (dys)functions. Among these PTMs, the O-β-linked N-acetylglucosaminylation (O-GlcNAcylation) modulates Tau phosphorylation and aggregation. We here focus on the role of the PHF-1 phospho-epitope of Tau C-terminal domain that is hyperphosphorylated in AD (at pS396/pS404) and encompasses S400 as the major O-GlcNAc site of Tau while two additional O-GlcNAc sites were found in the extreme C-terminus at S412 and S413. Using high resolution NMR spectroscopy, we showed that the O-GlcNAc glycosylation reduces phosphorylation of PHF-1 epitope by GSK3β alone or after priming by CDK2/cyclin A. Furthermore, investigations of the impact of PTMs on local conformation performed in small peptides highlight the role of S404 phosphorylation in inducing helical propensity in the region downstream pS404 that is exacerbated by other phosphorylations of PHF-1 epitope at S396 and S400, or O-GlcNAcylation of S400. Finally, the role of phosphorylation and O-GlcNAcylation of PHF-1 epitope was probed in in-vitro fibrillization assays in which O-GlcNAcylation slows down the rate of fibrillar assembly while GSK3β phosphorylation stimulates aggregation counteracting the effect of glycosylation.
O-GlcNAc proteins:
TAU
Species: Homo sapiens
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Lu S, Yin X, Wang J, Gu Q, Huang Q, Jin N, Chu D, Xu Z, Liu F, Qian W. SIRT1 regulates O-GlcNAcylation of tau through OGT. Aging 2020 12(8) 32310828
Abstract:
Tau is modified with O-GlcNAcylation extensively in human brain. The O-GlcNAcylation levels of tau are decreased in Alzheimer's disease (AD) brain. Sirtuin type 1 (SIRT1) is an enzyme that deacetylates proteins including transcriptional factors and associates with neurodegenerative diseases, such as AD. Aberrant SIRT1 expression levels in AD brain is in parallel with the accumulation of tau. cAMP response element binding protein (CREB), a cellular transcription factor, plays a critical role in learning and memory. In this present study, we found SIRT1 deacetylates CREB and inhibits phosphorylation of CREB at Ser133. The inactivated CREB suppresses OGT expression and therefore decreases the O-GlcNAcylation of tau and thus increases the phosphorylation of tau at specific sites. These findings suggest that SIRT1 may be a potential therapeutic target for treating tauopathies.
O-GlcNAc proteins:
TAU
Species: Homo sapiens
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Huo B, Zhang W, Zhao X, Dong H, Yu Y, Wang J, Qian X, Qin W. A triarylphosphine-trimethylpiperidine reagent for the one-step derivatization and enrichment of protein post-translational modifications and identification by mass spectrometry. Chemical communications (Cambridge, England) 2018 54(98) 30379171
Abstract:
We report a new reagent that is capable of both chemical derivatization and selective enrichment of azide-labeled PTM peptides for sensitive identification by mass spectrometry (MS). Facile sample recovery, enhanced ionization and fragmentation in MS of the enriched PTM peptides are achieved, which leads to the identification of 3293 O-GlcNAc peptides and the location of 1706 sites in HeLa cells and efficiently expands the current mapping scale.
O-GlcNAc proteins:
MEIKN, UH1BL, SHOT1, TTC24, PIPSL, HFM1, ZN320, NBAS, CQ102, VWA8, SBNO1, Z804B, CC14C, SH321, EFCB5, XIRP2, ODAD3, CNOT1, BDP1, ANR62, CC88B, AN33B, NKX26, PGP, F186A, ARRD5, FBP12, ANKUB, CI092, CE052, FA47D, SMHD1, LRIQ4, GLOD5, ZN233, SH2D7, MARHB, TTLL8, BTBDB, A30BL, ZSWM8, P121C, ERI2, PP2D1, CEA18, R212B, YV023, ZN727, VGLL3, YD021, RUXGL, IQAK1, MAGBH, FOXO6, FHAD1, SRRM5, ZN879, S14L6, CJ142, KRBX1, MCRI1, FONG, CE067, F227A, CRCC2, KIF2A, MYO1C, EYA2, AP3B1, SPT5H, TAF4, HIP1, CDC7, ST1C2, WASL, IPO5, EMAL1, P3C2A, EXOC5, PSDE, USP9Y, BCL9, CAC1A, PITM1, MPP10, TRI38, NDKM, ARI1A, NCKP5, FCHO1, SOCS3, TRAD1, RHG33, TYB4Y, UTY, ENC1, ZN197, APAF, TERT, CHK1, GNB5, TCRG1, UN13B, RASM, PPE1, IFIT3, IKKB, TIM23, HGS, AURKA, MYPT1, XPO1, IPP2C, ZN646, PDZD2, SPTN2, SET1A, TRNK1, PER2, SYNJ2, ZN536, IKKA, TBX3, ARPC2, TBXT, VILL, NKRF, ZN185, CASC3, CLIC2, ACOX3, NPHP1, OGT1, PPM1D, RA51B, SHIP2, EIF3D, IPO8, MSH4, MAGB4, ARPC5, PER1, ZSC9, ZZEF1, TET3, SI1L1, PRP4, SERA, IRAK2, PSMD3, TEX33, AP5Z1, MTSS1, PAX4, WDR62, PRPF3, SYNJ1, IF4G3, KCAB3, E41L2, FOXO3, TGM5, SYT7, PPIP1, CHM2A, PLRG1, LDB2, BUB1, HTSF1, STX6, ENSA, CPSF5, CREB3, AK1BA, KALRN, MYPT2, MED14, SOX15, KLK8, PRKN, SMCA5, ZC3H1, TYW4, LZTS3, GANP, KIF1B, PHLP1, ZN861, BRNP1, MPZL2, OGA, VINEX, HNRPQ, RNBP6, GMDS, REV3L, JAK2, MAFK, MUSC, CTND1, HPGDS, Z354A, RT14, PQBP1, BRD4, ABCB7, PLCH2, SRGP2, DEN4B, N4BP1, ROCK2, COBL, CPNE3, ZBED4, LIPA3, OBSL1, BRE1B, PHF2, ZC11A, CLU, DJC13, ANR17, SIN3B, LIPA2, LIPA4, ZN253, ZN217, FLNB, NCOR1, NDUS6, RM33, DPOLQ, CDC45, MPPB, USH2A, SRS10, GEMI, ECI2, TAF5L, ZN821, DAB1, MYCB2, U520, OFD1, UTP20, NU155, CMC1, PALM, ZN189, CCNK, SERF1, PIAS1, DNJC8, RAD17, ANXA9, CLPX, SEGN, CDKL5, NEBL, S14L2, RECQ4, RECQ5, RMP, AL1A2, TOM70, TOX4, MICA2, K0754, FCSD2, SRBS2, SASH1, CSCL1, LRIG2, SUN1, PRP6, PCF11, KDM4B, CE152, SOX30, UBR5, REC8, DUS14, NDUB8, KLHL2, LETM1, MBD4, KAT7, KCNH1, SMC2, IPO7, SLU7, SVIL, NPT2B, LCA5L, FMNL1, PCNT, CNOT4, CPSF4, NFAC1, EYA4, BRD1, HERC2, HS74L, DDX58, ZMYM6, BAG3, DCMC, DDAH2, TGM3L, TBX18, TBX6, BCL10, APBA3, NSD2, GSHR, CRYAB, LMNA, SPTA1, ESR1, ANGI, TDT, CYTB, GCR, SODM, MYCN, G3P, P53, HSPB1, ARGI1, PCCB, RLA2, RLA0, RPC4, K1C18, FYN, NFL, NFM, PERT, CRGC, SYEP, ANXA6, RHOC, GLI1, PFKAM, CATG, INHBA, VIME, ANXA5, SNRPA, VILI, CN37, HMOX1, DLDH, HXB7, DPOLA, IFIT2, WEE2, FBSP1, BNIP5, AN34C, ACSM4, PRR29, F90AO, YT014, R10B1, GRL1A, F200B, DERPC, CTF8, ZN888, RGPD2, GIMD1, ZN728, CH088, AT8OS, MYBA, ARAF, ODP2, TAU, KAP0, HEM4, HSP7C, SPTB1, TOP2A, VDR, DMD, ADHX, NFH, TPR, ANXA3, SKIL, NR2C1, HXD8, ENOB, T2FB, MTDC, 3BHS1, GFAP, KPYM, HXB1, PO2F1, ERF3A, EZRI, PHKG2, DESP, ANK1, NCPR, CBPE, PLCG2, ZFX, ZNF14, ZN708, ZNF17, ZNF19, ZNF20, ZKSC1, ZNF28, ZNF30, ZSC20, ZNF7, KPCA, UBF1, ATF7, DDX5, LOX12, EGR1, ARY1, SON, ATF1, ATF6A, NUCL, HXK1, TNNI3, HME2, SL9A1, RAB3B, LMNB1, GRAH, NEBU, AOFA, ZNF10, TGM2, MUTA, PERL, ROA2, CBL, KAPCB, HEMH, XPA, CRCM, SAHH, IF4B, PAX7, GATA2, CPT2, RIR1, EF1B, CCNC, DNJB2, PSA1, MOES, DDX6, RAE2, PTBP1, SYVC, 1433T, ARNT, RFA1, MAP4, PSB9, TMOD1, ITPI2, HXD9, ERCC5, EPHB2, PTN6, SHC1, KDM5A, LMOD1, TYK2, PRDX6, CDC27, WEE1, MPIP1, MPIP2, NKTR, CLIP1, RPB2, KAP1, CPSM, ZEP2, CASPE, 1433B, STIP1, FOXN2, TF2H1, C2TA, LSP1, DUT, GCYA2, MCM7, HYES, MPI, CTNA1, NOS2, SPB6, MERL, RFC4, RFC1, ADML, RORA, CBS, GDE, ACTN2, ADDB, NU214, DEK, CYLC1, ATP7B, SOX5, SOX11, ZNF93, VATE1, 8ODP, LONM, PGM1, GNL1, PEDF, ODO2, SRP14, IF4A3, SMBP2, CUX1, TYRP2, MLH1, STAT3, UBP8, PEX19, ECHA, ETV6, STAT6, AF9, HELZ, LPPRC, HD, ECE1, MUC18, BTD, MAGB1, KSYK, UBP5, KI67, KPB2, KPB1, RECQ1, IF2M, BRCC3, RL28, MAP1B, NEDD4, UTRN, CAPZB, CDX1, RL29, UCRI, PPCE, RFX5, PI42A, RXRG, NRIP1, PRC2A, CCN3, AL9A1, NASP, RM19, CENPF, MCM2, YLPM1, VPS41, NUMB, CLK1, NU153, RBP2, RGS3, RGS7, TSC2, TAF6, DNLI3, ETV1, DYN2, TUB, TCPD, PAPOA, PLCD1, ZNF80, ZNF81, ZNF84, BRCA2, RENBP, MECP2, HCFC1, SSDH, AFF2, AFF3, MYOM1, HNRPM, NCBP2, MP2K6, GDIR2, AGFG1, ZN135, ZN142, ZN143, RBM5, SPSY, HXK2, DGKQ, THOP1, TXTP, PPP5, LIMK2, SMTN, DPOG1, ICLN, BLM, PDE1A, GALC, KAD2, IF5, NR1H2, AFAD, AF17, ADK, DSRAD, UCP3, DLX1, SYMC, ATP5I, HDAC4, PEX3, PER3, RP1, SIK1, PRD15, UBS3A, NAC3, NU107, SNX16, RGS8, FBXW4, SESN2, TIRAP, H2B1D, CU082, MCCD1, EIF3E, PTEN, IF4A1, SNP25, DEST, ARP2, ISL1, REC21, STXB1, 1433G, UBP46, TIM10, PRS4, PRS10, ERF1, GAK8, RS4X, RBX1, TRA2B, ACTG, F193A, NOP14, RBM6, GTF2I, DLG4, IRX6, GSTO1, RELN, PRKDC, ELF3, MAP1A, SIM1, SSBP2, TMF1, RT05, RT11, RT09, HMGN5, SKOR1, FOXK1, PRR5, DAB2, EFNB1, RBM10, RBM3, VIGLN, BORG5, FANCC, CLH1, HSF1, MYPC1, U2AF1, SPTB2, TIAR, SET, FOXK2, RELB, AMPD2, ANK2, TFAP4, XPC, OCRL, AK17A, MEF2B, SP2, CENPE, KIF23, MMSA, ID2, ZNF45, APBA1, HEN1, FKBP4, RL6, TOP2B, DYST, KMT2A, CENPC, ERCC6, TAP1, ZN117, ARI5A, IF4G1, TLE3, TLE4, UBE3A, DYN1, SRS11, CALD1, RN5A, EMAL5, BTK, EXOS9, MTG8, GABPA, CDK18, ZO1, TRHY, PDE4B, SPAG1, KHDR1, DPOE1, SRSF4, GOGA3, PDE4C, DEMA, PDE4D, RBL2, ZN844, ACSM1, DMWD, EP300, AHNK, ZNFS1, FCHO2, PLCX2, DYH14, K2012, CGNL1, CC173, FP100, MESP2, NEXN, CPSF1, MPPA, SCRN1, TF3C1, HYAL1, BPTF, SFSWA, SF3A3, DPYD, TP53B, IFRD2, ILF3, EPS8, FOXC1, ANK3, GNDS, SEC20, NFX1, TIAM1, AF1Q, AKAP6, PRDM2, CAF1A, TRAF3, AIMP2, CBX3, DDX10, TBX2, ERCC8, GPS2, SBP1, NMI, PABP4, CD5R2, PPIL2, MB211, PM2P3, ORC1, ORC2, SNTB2, PPIG, FKBP5, MYO9B, GAB1, BIRC2, PICAL, SQSTM, BFSP2, PRP4B, ATR, SNW1, IQGA2, MTMR1, CUL4B, ASPP2, DYR1A, PTC1, RAB32, FHL1, FHL3, PM2PB, CAC1S, THOC5, NCOA4, SPTN1, KCNC3, CDK13, CKAP5, CYLC2, DAG1, SRTD2, MORC3, SAFB2, UBP2L, SCRIB, DOC2B, DOCK1, BTG3, ZMYM3, DYHC1, EI2BA, SRC8, FAK2, FLNC, FA50A, GRB14, HES1, NF2L1, FAT1, DHX8, MCM6, ITPR3, ZN266, ZN235, ZN460, PLSI, PUM1, KANK1, MELK, SMC1A, RRP1B, NCOA6, GSE1, PSF1, BMS1, LBR, STAT4, CBX2, KIF22, MEF2D, MTF1, MYPC3, NC2A, NFIX, ZN638, NOLC1, NR1D2, PSME4, CUL7, SLMAP, GAPD1, FRPD4, CND2, MO4L2, SUZ12, R3HD1, SNX17, S39AE, LRC14, DPOD3, IF4H, KIF14, EEA1, CD5R1, NCF4, PLCL1, PDK1, PLCB4, PLEC, PTPRR, PWP2, IRF4, ZMY11, L2GL1, UBE3C, PUM3, DLGP5, RBY1F, KS6A1, SAFB1, SYCP1, PP1R7, SP17, MED22, TAF1C, NCOA2, TRIPB, PCH2, MED1, JHD2C, ZN174, DLG2, CEBPE, TAB1, STXB2, ZFHX3, ZBTB6, ZYX, SEPT7, ADRM1, AINX, PSMD5, PKN2, TAF12, CDC37, B2LA1, TAF9, MAPK3, TBR1, CP1B1, DGKD, THTR, PCKGM, ZN827, LONF1, EX3L4, TPRXL, GEN, HNRL2, LONF2, SAMTR, PDS5A, MOONR, QSER1, WASC4, EX3L2, TECT1, ERC6L, RGPA2, D19L1, ZXDC, CCD57, PWP3A, ATG2A, FHOD3, IF2GL, KLH38, HFE, BTBDG, LRRF1, RFX4, LRRK1, F161A, INAVA, MA7D1, PKHG6, CHD9, TBC25, C144B, OD3L2, ZN718, AL1L2, P12L1, PTHB1, GON4L, GRDN, GVQW3, PAR14, CP100, ZN404, CL036, SPAS1, SV2C, YJ016, ZFP69, CE022, C2CD3, KMT5B, LARP7, HYDIN, KCD21, IQCC, PLCH1, FIL1L, ARI4B, GRAP1, Z658B, PAP1L, TIGD2, FNDC1, VWA3B, PAN2, CN177, Z585B, SBK1, SNUT2, TYW2, FAKD1, C2CD6, SGO2, CC178, ODFP2, CAVN4, FSIP2, UROL1, ZN628, TRI61, ESCO1, ZN789, BCORL, ZMAT1, PP6R3, DCA17, FSCB, K2026, ZC12B, NHSL2, ZN831, AKAP4, MTUS2, FA47A, MEIG1, PRC2B, RRP12, IQEC2, SPIN3, ZN506, DOP1, F209B, GASP1, DGKK, CYTSB, CD158, SPXN4, FBX47, TCHL1, TDIF2, ERIC3, LRRK2, SAPC1, CE170, PR15B, CJ055, SNPC4, CTSRE, NHSL1, F120S, C2D1B, TEX35, FA83B, SYRM, AXDN1, FKB15, AKND1, ZC3HD, MPP7, UBR4, ZN684, SWT1, SKT, CC183, RHG21, BEND3, UBAP2, PHF19, LITD1, F27D1, TSTD2, ER6L2, PPR26, ACBD5, UT14C, TUT4, DEP1A, CE162, FRY, ZBT37, MAGI3, KAD9, DDI2, MEI1, CC181, LIN9, ZN658, CROCC, CBPC2, MCAF2, RIF1, ZN468, SPXN1, OBSCN, NTM2D, CE350, RPRD2, SYDE2, KLD7A, BRE1A, MYOME, P210L, ZN318, A20A3, ZN691, PPRC1, SPO16, MYSM1, NTM1B, TAF3, SNX30, TASO2, KHDR2, ECM29, NAA35, MBNL2, OBI1, USPL1, F219B, RN123, FBX31, FBW10, ZKSC2, RN213, WDR25, CP135, Z385C, AR6P4, ARID2, TENS3, SPT2, FMN1, ANKS6, USF3, MSL1, CB016, CRBG3, FRPD2, RHG17, DUS29, C19L1, VIR, CYTSA, ZN660, REP15, URFB1, SP5, CARL2, K0930, JADE1, SNR48, CAPR2, SPOPL, CCSAP, PKHA7, ADNP2, IF5AL, GRHL2, ZN425, ACD10, IFIX, NIPBL, LIN54, R7BP, TET2, TEN4, Z280D, NAA16, RADX, K1841, ZSC25, SCMC1, ACSM5, JHY, CRCDL, SWAP1, ZN774, ZN544, JMJD6, CAVN1, FXL22, M18BP, CDC73, T2H2L, XRRA1, TTC41, NEK5, NFRKB, LMOD2, RL22L, PKN3, ERIC5, ANR16, FXL19, ZN880, TM10B, KLH35, PSRC1, BORA, IYD1, KCD18, BHLH9, FBX38, FOXR1, ARMD1, BRAT1, ZC3HE, LARP1, ATAD2, SPG17, RICTR, BRWD3, TSSK4, F111B, SAMD1, SARM1, KLH17, PADI6, C1TM, ANR12, ANR11, FIP1, SAS6, UD2A3, CWC27, LRIG3, MIC27, BI2L2, MCAF1, BCOR, MPRIP, ZY11A, NSMF, RBMS3, RPTN, DNMBP, GGYF2, CCNI2, ZN782, EMAL6, SYNE3, MASTR, CU136, MEX3B, ZNF66, ZN793, LN28B, CCD81, RN111, ZN704, BICL1, CC141, WDR87, ZN493, CO039, CCD73, SRCAP, ZN662, NBEL1, YD022, SHSA6, YO027, YJ005, TSH1, CBAR2, CG065, MSD1, K0408, CFA65, UBN2, BEND4, F205A, RHG27, FRMD7, FOXNB, RFX8, FGD6, MICLK, ANKS3, YS043, VP13C, UBP34, UBP31, UBP53, UBP43, ZN365, CEFIP, CENPU, SSH2, CEP68, SPT6H, RUFY3, ERIP6, DHX30, ZN765, MCM10, DOK3, GDPD3, RFIP2, FAKD5, OTU6A, ZN627, KDM3B, STRAA, MICA3, OTOP3, SSX7, U17L1, H2BWT, ZCCHV, GVIN1, TICRR, EFL1, PBIR2, SETX, KANL1, NUP54, PRIC2, ZN572, RGPD4, POGZ, ZFY16, MYCPP, TMC6, NUFP2, MAVS, CLAP1, DHX29, LIMS2, TT21B, HEAT3, CFA91, ZN438, HDGR2, EMSY, AKNA, RAI1, ANKAR, I2BP2, AB12B, SNX20, SPRE1, RBBP6, ANS1B, UBE3D, PTAR1, TCPR1, RABEK, HUWE1, YTHD3, FLIP1, TAF8, KHDC4, VP13B, S1A7A, PHLB2, CROL1, KAISO, ZN605, UBP37, K1328, RN180, PATL1, MYPN, PEG10, ATG4D, TTC7B, ISCA2, PABP2, LDB1, PB1, RIP, MARH3, NFE4, RIMS1, CATAC, NT5D3, CASZ1, VASH2, LUZP1, MORC1, MYPOP, NRAP, IQGA3, ZCH18, PACS2, MON1A, TSYL5, ZSC30, PARG, LIPB1, LONP2, RASF3, NLRC5, CHD1L, SKAP1, AROS, CDR2L, DAA11, EZHIP, CQ082, CIR1, HTR5A, ZFAN4, SNX32, HOGA1, DRC11, ZN761, GOLI, TRI50, Z354C, CD20B, KMT5C, ZN573, PRGC2, P66A, RASL3, MD12L, I2BP1, RB6I2, RIOX2, MY18B, RBM45, SIAH1, RELL1, LACC1, HID1, ANKY2, PSTK, VRK3, CROL2, PKHH2, AHNK2, TIAM2, AN18A, FMNL3, SAM9L, NAV3, NAV2, CCD50, FABD, MISP, HERC6, WDR75, MFN1, CCD60, TEX14, MA7D3, NXP20, CCD83, DNAI3, MGAP, GCC2, RP1L1, BRSK2, Z3H7A, TPH2, UBR2, ANKH1, SUGP1, SUGP2, KIBRA, GOR, CCAR1, SLF2, RM41, GPAM1, KLHL7, ETKMT, DDIAS, RB12B, ZC3H3, SMC5, DHX37, KBTB2, SPB1, NIM1, C144C, CKP2L, IHO1, SUV3, ERF3B, FANCM, ZZZ3, EXOC8, CF206, P20D2, DAAF8, CFA46, SAXO1, CG061, RTKN2, SAM14, KMT2E, DOCK3, ABI1, ASPM, F185A, CA087, IQCK, SPG16, SPART, SPICE, TTC5, TAGAP, RPTOR, EID3, AHI1, ZN567, ZN687, REXO1, S6OS1, CRPAK, CRBG2, THEM5, ANR35, CLASR, AN36B, RUSC2, CF223, RHG18, PARP8, EH1L1, METL4, CMYA5, VPS8, PALS1, SYNPO, FNBP4, RDHE2, PRS35, PGBD5, NIN, SPA6L, SPEM1, TT30B, LRC71, AF1L2, CERS5, SRBD1, TAB3, MACOI, MINY1, CCD33, TM148, ESX1, PACRL, TRIMM, TM217, ZN676, NANG2, ANR31, CNTD1, TEANC, ZN615, K1958, ENAH, CDYL2, CO056, ZN709, JMY, ZN454, ZN565, YV006, SR1IP, CDRT4, TAC2N, FA71D, FSIP1, ZN383, PNDC1, FA47B, MARHA, KBTB3, CI106, CAST3, ZBT38, CH058, SMYD1, UN13C, KY, CK072, ZN114, PAIRB, HJURP, SEN2, GLBL3, K0895, SMG8, RN214, Z280C, MROH1, PAPD5, CC168, ICA1L, EHBP1, CBPC5, RB15B, SMC1B, PHC3, BEND2, SIMC1, NSUN7, SRFB1, DDHD1, SP20H, CBPC3, ARMC2, PDZD8, ZN555, RTL9, DP13B, NAV1, WDR19, KMT2C, FBX22, SYNE1, BD1L1, FAD1, FLCN, PXT1, DBF4B, IPMK, ABHDB, DMBX1, FBH1, PJA1, KNL1, NEK11, KDM2B, ARK74, CLHC1, CFA61, NEDD1, RLA0L, ZFP28, THOC2, INADL, KI18A, ZNT5, SNIP1, WDR48, UHMK1, NEIL3, FA76A, ZN671, PRR7, PUM2, KLDC4, NANP, AT2L1, RBM46, PMFBP, CC110, ZN502, TBC15, ZN596, FA71B, FANK1, ZN507, PHOP1, ALMS1, DC2L1, CHD6, HUMMR, SP7, ACTT1, HELQ, DMXL2, DLG5, MIPT3, OTU7A, S26A7, ATS17, S3TC1, TBCK, PO210, CE192, GEMI5, FBF1, RPGF6, SMCR8, PARD3, PNISR, ZN483, DI3L1, ZN526, GIPC2, CP078, DUS19, THAP3, ZDHC1, TB22A, PDC6I, CO040, DCAF4, MITD1, TFB1M, TPC14, DC2I1, UBCP1, TRUB1, LMO7, CKAP2, CCNB3, ATX2L, PHIP, RT4I1, PALLD, CRGN, SYNE2, CNKR2, ASB10, ACO11, P66B, ASB17, BBX, CTBL1, ELYS, TITIN, TRIB2, SMG7, RTF1, IP6K1, PHYIP, DCNL4, P55G, NR4A3, PHF3, NDRG1, HS105, ZN592, PRP16, ANS1A, FAN, AKAP1, ZN75C, CENPI, PRCC, RREB1, HDAC2, DPF1, DPF3, REQU, CBP, SYMPK, HYAS2, KAT2A, RPGR, DDX17, KIFA3, NEO1, RAD50, RAB8B, ARHG2, IRF7, TF3B, DVL3, USP9X, CUL5, LPP, TP4A1, HGD, SMCE1, FBXW7, FBX32, TOP1M, TRI63, LMBL2, ZN622, 5NT3B, FBXW5, PSMG2, TEKT1, FAKD4, TET5B, C102A, RM24, SPSB4, ZUP1, CC74A, TTC28, R51A1, DACT3, SH3K1, PF21A, ELMO3, PINX1, CC049, S1PBP, ZN775, DOC10, ATG2B, ZBTB9, ROP1L, COAC, CHM4C, CC124, OPTN, S7A6O, GASP2, RMD1, OTUB2, ATG4C, DRC10, MTBP, RRFM, MTEF3, ELP4, HOOK2, MTMR8, ZN837, RL39L, MITOK, SGF29, RBM33, DTBP1, ZN503, ELMD3, THOC1, HMCES, IMP4, KLD7B, SCMH1, TOE1, MSD3, ZCCHL, TONSL, NTAQ1, PDLI5, PRR11, FMC1, C2AIL, INT4, SYNM, REXO5, GMPPA, GMCL1, ZN496, NGLY1, RBM41, TPD55, ESIP1, MAP6, ZN594, ZN469, ZN462, FEM1C, PGBD1, ZN521, TOPK, PRAC1, COX42, KCNS1, Z512B, ZFR, F167A, P12L2, CD036, NSD1, EP400, IFT74, SGCZ, CX058, CEP19, CH048, CL037, MRFL, Z354B, PRIPO, RMD2, CJ090, IFAS1, TEKT5, TEX55, FEAS2, CCDC7, CFA53, ZN512, CQ10A, NSE2, CE034, RIPR3, TEAN2, ZSWM3, YTDC1, ZNF48, F161B, F218A, TTC14, CK037, ZN578, PWP2A, DOCK7, ZN641, ZN582, ZFP3, LRRC7, BIRC8, INP4A, TSSK2, RBM14, ADCYA, IPP2L, ZN317, PNMA5, K1908, FMNL2, PUS7, F111A, PLIN4, SMG1, ALKB3, KI20B, RHG07, ATAD5, TEFM, RAB3I, ACRC, PRAM, MAGI1, RET7, PANX2, MED15, ERBIN, TRIB1, HMCN1, CRML, PRR25, LYSM1, CCNL2, SMC6, ZN607, ZN587, IWS1, SEBP2, RSF1, RUFY1, IMP2L, MINT, SETB2, ACOX2, AGAP2, EYA3, DNJC2, MPP9, M3K14, S10AD, SCAFB, ELF4, KLF6, PHB2, CHP1, KIF2C, LYST, ATX2, SMAD5, BARD1, NPAS1, EPAS1, TS101, CPNE1, SMO, EBP2, PKP2, AKAP9, ARP5L, SIN1, RNZ2, CMS1, SENP7, SLF1, COE4, ST4A1, ZSWM1, COR1B, LSMD1, SRSF8, PYGO2, FSP1, GPTC1, LLPH, SIKE1, TRI56, ZPBP1, BTBDA, TACO1, PIMRE, S2533, EFC4B, HAUS8, ALKB7, DIDO1, MTA3, DCNL5, RAMAC, FAP24, LRRC1, MED18, RCAF1, SCMC3, THUM3, CP250, KTNB1, PHF20, RUSC1, RIOK2, TIM21, KIFC1, HIRP3, TRAIP, FUND2, CYREN, CDCA7, MND1, CAR10, NADAP, GATA5, SYCP2, FANCJ, SRBS1, CARD6, ZN471, OSB10, RFIP5, SPZ1, CAR14, CAR11, T121B, TGT, TDRD1, TEX15, RNF17, STK31, UBP26, OSBL1, FACD2, AN30A, MAK16, SCAPE, DGC6L, RTF2, PECR, LRRC3, RNF26, SCOT2, RM01, ACE2, MSTRO, HYCCI, YTHD1, LRRC2, NEUL, PBX4, BCDO2, CEP41, SETD2, TBD2A, LDH6B, PANK2, NSD3, NUF2, PUS3, BARH1, OSBL7, UACA, REN3B, NIBA1, UBXN6, TRI15, TRIM4, F117A, SPEF2, LRCC1, ZFHX2, CFA74, AMRA1, CE295, ZY11B, TANC1, XPO4, GRIP2, ASXL3, CEP44, ZN407, SRCN1, CCSE1, WDR33, TGIF2, ROGDI, REXO4, NXF2, MFF, DRC3, CLPB, LSG1, NUAK2, NAT10, IQCN, ILKAP, SP130, UBP44, BRD8, RGAP1, PUS7L, ZCPW1, GZF1, BC11A, I2BPL, ISCU, RSPH9, VPS11, AL8A1, TARA, EPC1, CI037, PDCL3, ADNP, TNMD, RBP17, IPYR2, MIXL1, HIPK2, ZN106, E41LB, UBQL3, YI012, MOD5, GHITM, BOLA2, BORG4, UN45A, DSN1, CA198, RBSK, FN3K, WNK1, PLK3, E41L1, EMRE, PRD12, ZN644, VIAAT, THAP9, BICC1, CCD86, MYH16, CIAO3, ACSS3, BCAS3, ZN552, ASB8, SH24A, SMYD3, MB12B, ZN665, CCSE2, ZN430, NOL11, PAAT, MINY3, ECT2, F204A, CF208, ANKZ1, GHC1, PPIP2, MARH7, CNO10, SPE39, ANRA2, UNKL, RPF1, RPA2, SYCM, NMNA1, MLXIP, RENT2, BRF2, CLSPN, BCDO1, PRD16, PKHA1, AS3MT, TENS1, NMRL1, SPC25, TAF9B, Z286A, TPC, MRM3, GPBL1, CENPJ, ZBT20, HES4, NCOA5, TANC2, ZN532, SYTL2, MAGE1, K1586, ZSWM6, ZDBF2, CHD8, GPAT1, FBSL, ZN304, NDF4, HMX1, S40A1, GCM1, VTA1, EXOS4, UBN1, MKKS, MED4, SCRT2, CK016, PLCB1, A1CF, DDX4, DMRT3, INCE, PRDM9, BIN3, ENTP7, BIRC6, PDLI7, ACSA, DYRK4, ANM8, ASH1L, KLHL1, TSH2, SMYD2, SNRK, TBG2, STRN4, ZN277, LATS2, C42S1, PNO1, TOPRS, MBIP1, RAD18, HOME2, SALL1, ZN275, BRWD1, KLC4, AT8A2, DEPP1, CTSRZ, ZF64B, ECHD1, RBM12, ANKE1, MDN1, UFSP2, MITOS, OTULL, TYDP1, POTE1, DCA13, NUD15, RN19A, TYW1, EXOC1, UQCC1, MED17, TBC13, DJC11, INT7, FANCI, INT13, DZAN1, FAIM1, INT10, KTU, TBCC1, RPC2, RBM28, RBM22, BSDC1, WDR70, SLTM, SMOX, PIHD1, PARI, RMND1, BABA1, THG1, HPF1, IRAK4, TXN4B, NDUBB, MARH5, SYBU, MTMRA, TEX10, CNTLN, TRM1, CARF, NSE4A, DDX43, DPP3, ETAA1, ABI2, DYH9, HXC10, DACT1, FA53C, BCLF1, TAB2, CDK12, SMAL1, SACS, MAT2B, MYOF, ITSN2, ARHGC, CNOT2, VSX1, CWC15, RAI14, H2AW, RM27, VPS54, CAMP3, PHRF1, DAPLE, ZFAT, RELCH, DIP2B, JCAD, SLAI2, BAHC1, PAK5, CHD7, F135A, RRBP1, MAP10, CE126, CPSF2, KLHL9, SYLC, C2D2A, DISP3, TBC14, RBM27, KANL3, HECW2, STAR9, RERE, ANKY1, IMPCT, HNF6, HSFX1, RBX2, MYOTI, PRGC1, ARP21, GULP1, SAE2, POLK, DBF4A, NXF1, ZMYM2, REV1, ZNF70, S14L4, DAXX, ADDG, HYPDH, FXL17, CCD39, ABCF2, S23A2, AAKG2, KDM5B, SYWM, TCF20, SUN2, NDOR1, AFF4, SEPT9, UBQL2, IP6K2, NUFP1, SMPX, S30BP, MED13, PFD2, NRBP, FEZ2, EVL, CTNA3, XPO7, BAZ2B, BAZ2A, BAZ1B, HERC5, SIX4, ZMYM5, HACL1, STAG3, HOOK1, NGAP, ZN391, SALL4, CMC2, FBXL7, ZN112, DBNL, ZN229, ZN180, HSPB8, KS6A6, DBR1, FBXL4, FBXL2, GMEB2, PO2F3, GPTC8, C8AP2, FBX4, FBXW2, IKZF3, TRHDE, HDAC9, ACINU, AGO2, NUP50, ZHX1, DSE, SARDH, CFA45, AGO1, ZN236, ZN214, MKLN1, NRX1A, PADI1, ZN777, INTU, ZN608, WWC3, F184B, INO80, KDIS, MRTFB, ZBT21, NEB1, AT7L1, K1210, PKHG1, SHRM4, PKHH1, YETS2, CNOT6, HECD1, PKCB1, HSF4, PADI4, APC10, MYO6, SPAT2, KMT2B, CAN11, PHTF1, MAGD2, CSN3, TTF2, BSN, MACF1, SCAF8, TRI33, PHF8, K1107, LIMC1, TRI35, TNR6B, PLCL2, EXOC7, SMAG1, CE164, CBPC1, SATB2, UN13A, DICER, SRRM2, PA2G4, CD11A, CTND2, BAIP2, SCML2, RUVB2, CDYL, HIG1A, AKT3, PRLD1, PLAP, T53G5, ADIP, ICE1, EFR3B, PKHA6, MAST1, AMOL2, ZBTB1, KDM2A, FRM4B, FAN1, KLH20, CRYL1, AXIN2, GUAD, MAN1, TR150, MED16, ZBT32, MTO1, SYYM, ZBT12, CAB39, LC7L2, RBMX2, HDGR3, BOLA1, STA13, T22D4, RL36, C2CD2, HBS1L, ZN175, DMXL1, TRRAP, MTCL1, ZN451, WDR7, C170B, RIPR2, TLN2, DTNA, CRBG1, LAS1L, AFG32, PRC2C, PPME1, TRI17, CEP83, PAXB1, SP16H, MAGD1, KLF2, SNX5, LRRF2, FHOD1, IRAK3, NCOR2, GMEB1, BIG2, MD1L1, RM42, ATP23, SNCAP, CABIN, OAS3, NEMO, SQOR, NCOA3, NUMBL, Z780B, CCD61, ADSV, PCLO, SETBP, MORC2, NS1BP
Species: Homo sapiens
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Bourré G, Cantrelle FX, Kamah A, Chambraud B, Landrieu I, Smet-Nocca C. Direct Crosstalk Between O-GlcNAcylation and Phosphorylation of Tau Protein Investigated by NMR Spectroscopy. Frontiers in endocrinology 2018 9 30386294
Abstract:
The formation of intraneuronal fibrillar inclusions of tau protein is associated with several neurodegenerative diseases referred to as tauopathies including Alzheimer's disease (AD). A common feature of these pathologies is hyperphosphorylation of tau, the main component of fibrillar assemblies such as Paired Helical Filaments (PHFs). O-β-linked N-acetylglucosaminylation (O-GlcNAcylation) is another important posttranslational modification involved in regulation of tau pathophysiology. Among the benefits of O-GlcNAcylation, modulation of tau phosphorylation levels and inhibition of tau aggregation properties have been described while decreased O-GlcNAcylation could be involved in the raise of tau phosphorylation associated with AD. However, the molecular mechanisms at the basis of these observations remain to be defined. In this study, we identify by NMR spectroscopy O-GlcNAc sites in the longest isoform of tau and investigate the direct role of O-GlcNAcylation on tau phosphorylation and conversely, the role of phosphorylation on tau O-GlcNAcylation. We show here by a systematic examination of the quantitative modification patterns by NMR spectroscopy that O-GlcNAcylation does not modify phosphorylation of tau by the kinase activity of ERK2 or a rat brain extract while phosphorylation slightly increases tau O-GlcNAcylation by OGT. Our data suggest that indirect mechanisms act in the reciprocal regulation of tau phosphorylation and O-GlcNAcylation in vivo involving regulation of the enzymes responsible of phosphate and O-GlcNAc dynamics.
O-GlcNAc proteins:
TAU
Species: Homo sapiens
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Shen DL, Liu TW, Zandberg W, Clark T, Eskandari R, Alteen MG, Tan HY, Zhu Y, Cecioni S, Vocadlo D. Catalytic Promiscuity of O-GlcNAc Transferase Enables Unexpected Metabolic Engineering of Cytoplasmic Proteins with 2-Azido-2-deoxy-glucose. ACS chemical biology 2017 12(1) 27935279
Abstract:
O-GlcNAc transferase (OGT) catalyzes the installation of N-acetylglucosamine (GlcNAc) O-linked to nucleocytoplasmic proteins (O-GlcNAc) within multicellular eukaryotes. OGT shows surprising tolerance for structural changes in the sugar component of its nucleotide sugar donor substrate, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Here, we find that OGT uses UDP-glucose to install O-linked glucose (O-Glc) onto proteins only 25-fold less efficiently than O-GlcNAc. Spurred by this observation, we show that OGT transfers 2-azido-2-deoxy-d-glucose (GlcAz) in vitro from UDP-GlcAz to proteins. Further, feeding cells with per-O-acetyl GlcAz (AcGlcAz), in combination with inhibition or inducible knockout of OGT, shows OGT-dependent modification of nuclear and cytoplasmic proteins with O-GlcAz as detected using microscopy, immunoblot, and proteomics. We find that O-GlcAz is reversible within cells, and an unidentified cellular enzyme exists to cleave O-Glc that can also process O-GlcAz. We anticipate that AcGlcAz will prove to be a useful tool to study the O-GlcNAc modification. We also speculate that, given the high concentration of UDP-Glc within certain mammalian tissues, O-Glc may exist within mammals and serve as a physiologically relevant modification.
O-GlcNAc proteins:
A0A0D9R5K0, A0A0D9SE53, TAU, NUP62, TAB1, KCC4
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Hastings NB, Wang X, Song L, Butts BD, Grotz D, Hargreaves R, Fred Hess J, Hong KK, Huang CR, Hyde L, Laverty M, Lee J, Levitan D, Lu SX, Maguire M, Mahadomrongkul V, McEachern EJ, Ouyang X, Rosahl TW, Selnick H, Stanton M, Terracina G, Vocadlo DJ, Wang G, Duffy JL, Parker EM, Zhang L. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Molecular neurodegeneration 2017 12(1) 28521765
Abstract:
Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models. Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate the clinical development of OGA inhibitors for the treatment of tauopathies.
O-GlcNAc proteins:
TAU
Species: Homo sapiens
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Sharif S, Shi J, Bourakba M, Ruijtenbeek R, Pieters RJ. Measuring O-GlcNAc cleavage by OGA and cell lysates on a peptide microarray. Analytical biochemistry 2017 532 28571750
Abstract:
O-GlcNAcylation is a post-translational modification resulting from the addition of an N-acetylglucosamine moiety to the hydroxyl groups of serine and threonine residues of nuclear and cytoplasmic proteins. In addition, O-GlcNAcylated proteins can be phosphorylated, which suggests the possibility for crosstalk between O-GlcNAcylation and phosphorylation. Dysregulation of O-GlcNAcylation affects cell signaling, transcriptional regulation, cell cycle control and can e.g. lead to tumorigenesis and tumor metastasis. There is a strong demand for efficient analytical techniques to better detect and investigate this abundant modification and its role in cancer. Herein we demonstrated the utility of an O-GlcNAcylated peptide array to examine O-GlcNAcase (OGA) activity and substrate specificity of both purified protein as well cell lysates of different cancer cell lines. Using this microarray, we clearly observed OGA activity and also inhibition thereof by OGA inhibitor thiamet G. Interestingly, different levels of OGA activity were observed of lysates derived from different cancer cell lines. This suggests that the tool may be useful in cancer research and biomarker development.
O-GlcNAc proteins:
TAU, RBL2
Species: Homo sapiens
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Wang S, Yang F, Petyuk VA, Shukla AK, Monroe ME, Gritsenko MA, Rodland KD, Smith RD, Qian WJ, Gong CX, Liu T. Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease. The Journal of pathology 2017 243(1) 28657654
Abstract:
Protein modification by O-linked β-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer's disease (AD); however, detailed molecular characterization of this important protein post-translational modification at the proteome level has been highly challenging, owing to its low stoichiometry and labile nature. Herein, we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in postmortem human brain tissues with and without AD by the use of isobaric tandem mass tag labelling, chemoenzymatic photocleavage enrichment, and liquid chromatography coupled to mass spectrometry. A total of 1850 O-GlcNAc peptides covering 1094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. One hundred and thirty-one O-GlcNAc peptides covering 81 proteins were altered in AD brains as compared with controls (q <