TTLL4_MOUSE
ID TTLL4_MOUSE Reviewed; 1193 AA.
AC Q80UG8; A4Q9E6; Q5U4C4;
DT 10-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT 10-JAN-2006, sequence version 3.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=Tubulin monoglutamylase TTLL4 {ECO:0000303|PubMed:17499049};
DE EC=6.3.2.- {ECO:0000269|PubMed:17499049, ECO:0000269|PubMed:20530212, ECO:0000269|PubMed:21074048, ECO:0000269|PubMed:26829768};
DE AltName: Full=Protein monoglutamylase TTLL4 {ECO:0000305|PubMed:17499049};
DE AltName: Full=Tubulin--tyrosine ligase-like protein 4;
GN Name=Ttll4 {ECO:0000312|MGI:MGI:1914784}; Synonyms=Kiaa0173;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RC STRAIN=C57BL/6J; TISSUE=Testis;
RX PubMed=17499049; DOI=10.1016/j.molcel.2007.04.012;
RA van Dijk J., Rogowski K., Miro J., Lacroix B., Edde B., Janke C.;
RT "A targeted multienzyme mechanism for selective microtubule
RT polyglutamylation.";
RL Mol. Cell 26:437-448(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=129, C57BL/6J, and FVB/N; TISSUE=Brain;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 877-1193.
RC TISSUE=Embryonic tail;
RX PubMed=14621295; DOI=10.1093/dnares/10.4.167;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: III.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:167-180(2003).
RN [4]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=21074048; DOI=10.1016/j.cell.2010.10.014;
RA Rogowski K., van Dijk J., Magiera M.M., Bosc C., Deloulme J.C., Bosson A.,
RA Peris L., Gold N.D., Lacroix B., Grau M.B., Bec N., Larroque C.,
RA Desagher S., Holzer M., Andrieux A., Moutin M.J., Janke C.;
RT "A family of protein-deglutamylating enzymes associated with
RT neurodegeneration.";
RL Cell 143:564-578(2010).
RN [5]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=20530212; DOI=10.1083/jcb.201001024;
RA Lacroix B., van Dijk J., Gold N.D., Guizetti J., Aldrian-Herrada G.,
RA Rogowski K., Gerlich D.W., Janke C.;
RT "Tubulin polyglutamylation stimulates spastin-mediated microtubule
RT severing.";
RL J. Cell Biol. 189:945-954(2010).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=23897886; DOI=10.1083/jcb.201305041;
RA Bosch Grau M., Gonzalez Curto G., Rocha C., Magiera M.M., Marques Sousa P.,
RA Giordano T., Spassky N., Janke C.;
RT "Tubulin glycylases and glutamylases have distinct functions in
RT stabilization and motility of ependymal cilia.";
RL J. Cell Biol. 202:441-451(2013).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=26829768; DOI=10.1038/ni.3356;
RA Xia P., Ye B., Wang S., Zhu X., Du Y., Xiong Z., Tian Y., Fan Z.;
RT "Glutamylation of the DNA sensor cGAS regulates its binding and synthase
RT activity in antiviral immunity.";
RL Nat. Immunol. 17:369-378(2016).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=29593216; DOI=10.1038/s41467-018-03008-2;
RA Ye B., Liu B., Hao L., Zhu X., Yang L., Wang S., Xia P., Du Y., Meng S.,
RA Huang G., Qin X., Wang Y., Yan X., Li C., Hao J., Zhu P., He L., Tian Y.,
RA Fan Z.;
RT "Klf4 glutamylation is required for cell reprogramming and early embryonic
RT development in mice.";
RL Nat. Commun. 9:1261-1261(2018).
CC -!- FUNCTION: Monoglutamylase which modifies both tubulin and non-tubulin
CC proteins, adding a single glutamate on the gamma-carboxyl group of
CC specific glutamate residues of target proteins (PubMed:17499049,
CC PubMed:21074048, PubMed:20530212, PubMed:26829768). Involved in the
CC side-chain initiation step of the polyglutamylation reaction but not in
CC the elongation step (PubMed:17499049, PubMed:21074048). Preferentially
CC modifies beta-tail tubulin over the alpha-tubulin (PubMed:17499049).
CC Monoglutamylates nucleosome assembly proteins NAP1L1 and NAP1L4
CC (PubMed:17499049). Monoglutamylates nucleotidyltransferase CGAS,
CC leading to inhibition of CGAS catalytic activity, thereby preventing
CC antiviral defense function (PubMed:26829768). Involved in KLF4
CC glutamylation which impedes its ubiquitination, thereby leading to
CC somatic cell reprogramming, pluripotency maintenance and embryogenesis
CC (PubMed:29593216). {ECO:0000269|PubMed:17499049,
CC ECO:0000269|PubMed:20530212, ECO:0000269|PubMed:21074048,
CC ECO:0000269|PubMed:26829768, ECO:0000269|PubMed:29593216}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-glutamate + L-glutamyl-[protein] = ADP + gamma-L-
CC glutamyl-L-glutamyl-[protein] + H(+) + phosphate;
CC Xref=Rhea:RHEA:60144, Rhea:RHEA-COMP:10208, Rhea:RHEA-COMP:15517,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29973, ChEBI:CHEBI:29985,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:143622,
CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:17499049,
CC ECO:0000269|PubMed:20530212, ECO:0000269|PubMed:21074048,
CC ECO:0000269|PubMed:26829768};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60145;
CC Evidence={ECO:0000305|PubMed:17499049, ECO:0000305|PubMed:20530212,
CC ECO:0000305|PubMed:21074048, ECO:0000305|PubMed:26829768};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:A4Q9E8};
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:26829768}. Cell
CC projection, cilium {ECO:0000269|PubMed:17499049}. Cytoplasm,
CC cytoskeleton, cilium basal body {ECO:0000269|PubMed:17499049}.
CC Note=Located in cilia. In some cells, also found in basal bodies.
CC {ECO:0000269|PubMed:17499049}.
CC -!- TISSUE SPECIFICITY: Highly expressed in testis (PubMed:17499049).
CC Expressed in brain, heart, kidney, liver, lung, muscle and spleen
CC (PubMed:17499049). In the brain, expressed in ependymal cilia, the
CC cortex and the striatum (PubMed:23897886). Expressed in blastomere
CC (PubMed:29593216). {ECO:0000269|PubMed:17499049,
CC ECO:0000269|PubMed:23897886, ECO:0000269|PubMed:29593216}.
CC -!- DOMAIN: The flexible c-MTBD (cationic microtubule binding domain)
CC region mediates binding to microtubules. It is positively charged and
CC becomes ordered when bound to microtubules: it interacts with a
CC negatively charged patch on tubulin. The presence of positive charges
CC in the c-MTBD region is essential for proper binding.
CC {ECO:0000250|UniProtKB:Q14679, ECO:0000250|UniProtKB:Q6ZT98}.
CC -!- DOMAIN: Arg-722 is the main determinant for regioselectivity, which
CC segregates between initiases and elongases in all tubulin--tyrosine
CC ligase family. A glutamine residue at this position is found in
CC elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-
CC chain elongation, whereas an arginine residue is found in initiases
CC TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.
CC {ECO:0000250|UniProtKB:A4Q9E8}.
CC -!- DISRUPTION PHENOTYPE: Knockout mice show hypoglutamylation of KLF4
CC resulting in KLF4 proteasome-mediated degradation in early-stage
CC embryos and impaired early embryonic development.
CC {ECO:0000269|PubMed:29593216}.
CC -!- SIMILARITY: Belongs to the tubulin--tyrosine ligase family.
CC {ECO:0000305}.
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DR EMBL; AM690747; CAM84324.1; -; mRNA.
DR EMBL; BC044790; AAH44790.1; -; mRNA.
DR EMBL; BC085151; AAH85151.1; -; mRNA.
DR EMBL; AK129075; BAC97885.1; -; mRNA.
DR CCDS; CCDS15053.1; -.
DR RefSeq; NP_001014974.1; NM_001014974.1.
DR RefSeq; XP_006496287.1; XM_006496224.2.
DR RefSeq; XP_006496288.1; XM_006496225.2.
DR AlphaFoldDB; Q80UG8; -.
DR SMR; Q80UG8; -.
DR BioGRID; 212257; 1.
DR STRING; 10090.ENSMUSP00000037406; -.
DR iPTMnet; Q80UG8; -.
DR PhosphoSitePlus; Q80UG8; -.
DR EPD; Q80UG8; -.
DR MaxQB; Q80UG8; -.
DR PaxDb; Q80UG8; -.
DR PRIDE; Q80UG8; -.
DR ProteomicsDB; 298017; -.
DR Antibodypedia; 34286; 130 antibodies from 24 providers.
DR DNASU; 67534; -.
DR Ensembl; ENSMUST00000042125; ENSMUSP00000037406; ENSMUSG00000033257.
DR GeneID; 67534; -.
DR KEGG; mmu:67534; -.
DR UCSC; uc007bmy.1; mouse.
DR CTD; 9654; -.
DR MGI; MGI:1914784; Ttll4.
DR VEuPathDB; HostDB:ENSMUSG00000033257; -.
DR eggNOG; KOG2156; Eukaryota.
DR GeneTree; ENSGT00940000157916; -.
DR HOGENOM; CLU_007870_0_0_1; -.
DR InParanoid; Q80UG8; -.
DR OMA; FRTIREH; -.
DR OrthoDB; 219807at2759; -.
DR PhylomeDB; Q80UG8; -.
DR TreeFam; TF313087; -.
DR BRENDA; 6.3.2.B24; 3474.
DR Reactome; R-MMU-8955332; Carboxyterminal post-translational modifications of tubulin.
DR BioGRID-ORCS; 67534; 4 hits in 73 CRISPR screens.
DR ChiTaRS; Ttll4; mouse.
DR PRO; PR:Q80UG8; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q80UG8; protein.
DR Bgee; ENSMUSG00000033257; Expressed in dorsal pancreas and 221 other tissues.
DR ExpressionAtlas; Q80UG8; baseline and differential.
DR Genevisible; Q80UG8; MM.
DR GO; GO:0097731; C:9+0 non-motile cilium; IDA:MGI.
DR GO; GO:0036064; C:ciliary basal body; IDA:MGI.
DR GO; GO:0005929; C:cilium; IBA:GO_Central.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0070739; F:protein-glutamic acid ligase activity; IDA:UniProtKB.
DR GO; GO:0015631; F:tubulin binding; IDA:UniProtKB.
DR GO; GO:0070740; F:tubulin-glutamic acid ligase activity; IDA:UniProtKB.
DR GO; GO:0000226; P:microtubule cytoskeleton organization; IBA:GO_Central.
DR GO; GO:0018200; P:peptidyl-glutamic acid modification; IDA:UniProtKB.
DR GO; GO:0018095; P:protein polyglutamylation; IDA:UniProtKB.
DR GO; GO:0120222; P:regulation of blastocyst development; IMP:MGI.
DR InterPro; IPR004344; TTL/TTLL_fam.
DR InterPro; IPR027748; TTLL-4.
DR PANTHER; PTHR12241:SF145; PTHR12241:SF145; 1.
DR Pfam; PF03133; TTL; 1.
DR PROSITE; PS51221; TTL; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell projection; Cilium; Cytoplasm; Cytoskeleton; Ligase;
KW Magnesium; Metal-binding; Microtubule; Nucleotide-binding; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..1193
FT /note="Tubulin monoglutamylase TTLL4"
FT /id="PRO_0000212443"
FT DOMAIN 599..942
FT /note="TTL"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00568"
FT REGION 1..37
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 468..535
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 806..807
FT /note="L-glutamate"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT REGION 913..1027
FT /note="c-MTBD region"
FT /evidence="ECO:0000250|UniProtKB:Q14679"
FT REGION 943..966
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1092..1193
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 20..37
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 501..531
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 943..963
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1092..1122
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1129..1193
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 716
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 722..723
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 722
FT /ligand="a protein"
FT /ligand_id="ChEBI:CHEBI:16541"
FT /ligand_part="L-glutamate residue"
FT /ligand_part_id="ChEBI:CHEBI:29973"
FT /ligand_part_note="L-glutamate acceptor residue in protein
FT target"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 744..747
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 757..759
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 783
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 804..805
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 828
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 888
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 901
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 901
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 903
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 919
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT SITE 722
FT /note="Essential for specifying initiation versus
FT elongation step of the polyglutamylase activity"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT MOD_RES 686
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14679"
SQ SEQUENCE 1193 AA; 132530 MW; E3C6FC5653D0E24E CRC64;
MASAGTEHYS IGLRRGNSFK QRHPSGTVSA SPSEKPSEVK VWSQAHQQVK PIWKLEKKHV
GTLSAGLGTS FLGVPSQPAY FLCPSTLCSS GTTAVIAGHS NPCYLQSLPN LFSNTLLYRR
TNVRQKPYQQ LESFCLRSSP SEKRSFSLPQ KGLPVSVTAN KATSSTVFPM AQPMATSPTD
PYLSLAAAGE NPSRKSLASA ISGKIASPLS YKPMLNNNSF MRPNSTKVPL SQATDGLKPV
SSPKIQPVSW HHSGGTGDCV PQPGDHKVPQ NIATVLDDVT APITPSIPST LNISTASVTS
SQCSQSNFRM EAHPCGLDEN PDSQSATKEV HFTEAVRKLA EKGLEKMPRQ GYQFEQACFV
NPSFQWGLLN RSRRWKPLMG QRFPQEDIGL DSAILPGTSD TLGLDSTVFC TKRISIHLLA
SHVHGLNPSP ACGSAVDPQV LGEDRAPVPP SSLQPLGVAE VATRLSSVHL DQPGKEPEEA
KDLNSCTKGG GSATDLQPNQ VEPEDTEDEL GDGLEDSCSH DENEEEEGDS ECSSLSVVSP
SESVALISRN CVDLMSKSLP NHEKVVRPAL IYSLFPNVTP TIYFGTRDER VEKLPWEQRR
LLRWKMSTVT PNIVKQTIGR SHFKISKRND DWLGCWGHHM KSPGFRSIRE HQKLNHFPGS
FQIGRKDRLW RNLSRMQSRF GKKEFSFFPQ SFILPQDSKL LRKAWESSSR QKWIVKPPAS
ARGIGIQVIH KWSQLPKRRP LLVQRYLHKP YLISGSKFDL RIYVYVTSYD PLRIYLFSDG
LVRFASCKYS PSMKSLSNKF MHLTNYSVNK KNTEYQANAD ETACQGHKWA LKALWNYLSQ
KGINSDAIWE KIKDVVVKTI ISSEPYVTNL LKLYVRRPYS CHELFGFDIM LDENLKPWVL
EVNISPSLHS NSPLDISIKG QMIRDLLNLA GFVLPNMEDI ISSSSSPSSS SGSSTSLPSS
PRDKCQMTPE HFTAQKMKKA YYLTQKIPDQ DFYASVLDVL TPDDVRVLVE MEDEFSRRGQ
FERIFPSRIS SRYLRFFEQP RYFNILTTQW EQKYHGNKLK GVDLLRNWCY KGFHTGIVSD
SAPLWSLPTS LMTTSKGDGT PNSASKSRKK SASEGTTLSS EDRSTPKSKK SQAGLSPISR
KTLSSRSNEN TSKQSKRSTP GLPVLKYSGQ SSRLSAASAS QSVTDSRLTA VSS
