TTLL8_HUMAN
ID TTLL8_HUMAN Reviewed; 850 AA.
AC A6PVC2; B5MDV0;
DT 10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
DT 08-MAR-2011, sequence version 4.
DT 03-AUG-2022, entry version 107.
DE RecName: Full=Protein monoglycylase TTLL8 {ECO:0000250|UniProtKB:A4Q9F1};
DE EC=6.3.2.- {ECO:0000250|UniProtKB:A4Q9F1};
DE AltName: Full=Tubulin--tyrosine ligase-like protein 8 {ECO:0000250|UniProtKB:A4Q9F1};
GN Name=TTLL8 {ECO:0000312|HGNC:HGNC:34000};
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 296-551 (ISOFORM 1).
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
CC -!- FUNCTION: Monoglycylase which modifies both tubulin and non-tubulin
CC proteins, adding a single glycine to the gamma-carboxyl groups of
CC specific glutamate residues to generate monoglycine side chains within
CC the C-terminal tail of target proteins. Not involved in elongation step
CC of the polyglycylation reaction. Preferentially monoglycylates alpha-
CC tubulin over beta-tubulin. Together with TTLL3, mediates microtubule
CC glycylation of primary and motile cilia, which is essential for their
CC stability and maintenance. Together with TTLL3, glycylates sperm
CC flagella which regulates axonemal dynein motor activity, thereby
CC controlling flagellar beat, directional sperm swimming and male
CC fertility. Monoglycylates non-tubulin proteins such as ANP32A, ANP32B,
CC SET, NCL and NAP1. {ECO:0000250|UniProtKB:A4Q9F1}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + glycine + L-glutamyl-[protein] = ADP + glycyl-L-
CC glutamyl-[protein] + H(+) + phosphate; Xref=Rhea:RHEA:67180,
CC Rhea:RHEA-COMP:10208, Rhea:RHEA-COMP:17207, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29973, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57305, ChEBI:CHEBI:167890, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000250|UniProtKB:A4Q9F1};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67181;
CC Evidence={ECO:0000250|UniProtKB:A4Q9F1};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:A4Q9E8};
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
CC {ECO:0000250|UniProtKB:A4Q9F1}. Cell projection, cilium
CC {ECO:0000250|UniProtKB:A4Q9F1}. Cytoplasm, cytoskeleton, cilium axoneme
CC {ECO:0000250|UniProtKB:A4Q9F1}. Cytoplasm, cytoskeleton, flagellum
CC axoneme {ECO:0000250|UniProtKB:A4Q9F1}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=A6PVC2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=A6PVC2-2; Sequence=VSP_054007, VSP_054008, VSP_054009;
CC -!- DOMAIN: Two conserved structural elements specific among
CC monoglycylases, IS1 and IS2, are involved in glycyl chains initiation.
CC Two conserved structural interfaces likely constitute the binding
CC platforms for tubulin tail and microtubule.
CC {ECO:0000250|UniProtKB:A4Q9F1}.
CC -!- DOMAIN: Arg-360 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 -!- CAUTION: TTLL3 and TTLL8 monoglycylase-mediated glycylation of tubulin
CC was initially reported to play a role in ependymal motile ciliary
CC maintenance (By similarity). However, contradictory results were later
CC observed (By similarity). {ECO:0000250|UniProtKB:A4Q9F1}.
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DR EMBL; AL022327; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CR745100; -; NOT_ANNOTATED_CDS; mRNA.
DR AlphaFoldDB; A6PVC2; -.
DR SMR; A6PVC2; -.
DR STRING; 9606.ENSP00000392252; -.
DR iPTMnet; A6PVC2; -.
DR PhosphoSitePlus; A6PVC2; -.
DR BioMuta; TTLL8; -.
DR EPD; A6PVC2; -.
DR MassIVE; A6PVC2; -.
DR PaxDb; A6PVC2; -.
DR PeptideAtlas; A6PVC2; -.
DR PRIDE; A6PVC2; -.
DR Antibodypedia; 28278; 44 antibodies from 11 providers.
DR Ensembl; ENST00000266182.10; ENSP00000266182.6; ENSG00000138892.11. [A6PVC2-2]
DR UCSC; uc062fiv.1; human. [A6PVC2-1]
DR GeneCards; TTLL8; -.
DR HGNC; HGNC:34000; TTLL8.
DR HPA; ENSG00000138892; Tissue enriched (testis).
DR MIM; 619193; gene.
DR neXtProt; NX_A6PVC2; -.
DR PharmGKB; PA162407295; -.
DR VEuPathDB; HostDB:ENSG00000138892; -.
DR eggNOG; KOG2157; Eukaryota.
DR GeneTree; ENSGT00940000162265; -.
DR InParanoid; A6PVC2; -.
DR OMA; RMAFIED; -.
DR PhylomeDB; A6PVC2; -.
DR TreeFam; TF313087; -.
DR PathwayCommons; A6PVC2; -.
DR Reactome; R-HSA-8955332; Carboxyterminal post-translational modifications of tubulin.
DR Pharos; A6PVC2; Tdark.
DR PRO; PR:A6PVC2; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; A6PVC2; protein.
DR Bgee; ENSG00000138892; Expressed in right testis and 34 other tissues.
DR ExpressionAtlas; A6PVC2; baseline and differential.
DR GO; GO:0005930; C:axoneme; ISS:UniProtKB.
DR GO; GO:0005929; C:cilium; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW.
DR GO; GO:0015630; C:microtubule cytoskeleton; ISS:UniProtKB.
DR GO; GO:0036126; C:sperm flagellum; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0070735; F:protein-glycine ligase activity; ISS:UniProtKB.
DR GO; GO:0070736; F:protein-glycine ligase activity, initiating; ISS:UniProtKB.
DR GO; GO:0060271; P:cilium assembly; IBA:GO_Central.
DR GO; GO:0003341; P:cilium movement; IBA:GO_Central.
DR GO; GO:0030317; P:flagellated sperm motility; ISS:UniProtKB.
DR GO; GO:0018094; P:protein polyglycylation; ISS:UniProtKB.
DR InterPro; IPR004344; TTL/TTLL_fam.
DR Pfam; PF03133; TTL; 1.
DR PROSITE; PS51221; TTL; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; ATP-binding; Cell projection; Cilium; Cytoplasm;
KW Cytoskeleton; Flagellum; Ligase; Magnesium; Metal-binding; Microtubule;
KW Nucleotide-binding; Reference proteome.
FT CHAIN 1..850
FT /note="Protein monoglycylase TTLL8"
FT /id="PRO_0000340645"
FT DOMAIN 222..580
FT /note="TTL"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00568"
FT REGION 1..29
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 228..254
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 627..652
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 229..254
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 354
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 360..361
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 360
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 392..395
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:B2GUB3"
FT BINDING 405..407
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 449..450
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 527
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 540
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:B2GUB3"
FT BINDING 540
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 540
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT BINDING 542
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT SITE 360
FT /note="Essential for specifying initiation versus
FT elongation step of the glycylase activity"
FT /evidence="ECO:0000250|UniProtKB:A4Q9E8"
FT VAR_SEQ 1..53
FT /note="MEPERKGLSLASSSDGDGREENKLKQGISQDLASSSRLDRYKIARQLTEKAI
FT K -> MRLLDGKQTSRYSENAC (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_054007"
FT VAR_SEQ 313..326
FT /note="HGDAFISNSRNYFS -> QVPLGSSIVLCIFKIQKVMMSFEPPTARDR (in
FT isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_054008"
FT VAR_SEQ 362
FT /note="R -> RGESP (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_054009"
FT VARIANT 127
FT /note="L -> W (in dbSNP:rs59727397)"
FT /id="VAR_061867"
FT VARIANT 191
FT /note="R -> H (in dbSNP:rs17013076)"
FT /id="VAR_057316"
FT VARIANT 294
FT /note="E -> K (in dbSNP:rs9628315)"
FT /id="VAR_057317"
SQ SEQUENCE 850 AA; 94676 MW; 5867C8684801DBDD CRC64;
MEPERKGLSL ASSSDGDGRE ENKLKQGISQ DLASSSRLDR YKIARQLTEK AIKEKKIFSI
YGHYPVVRAA LRRKGWVEKK FHFLPKVIPD VEDEGARVND DTCAKVKENQ EMALEKTDNI
HDVMSRLVKN EMPYLLWTIK RDIIDYHSLT YDQMLNHYAK TASFTTKIGL CVNMRSLPWY
VPANPDSFFP RCYSLCTESE QQEFLEDFRR TMASSILKWV VSHQSCSRSS RSKPRDQREE
AGSSDLSSRQ DAENAEAKLR GLPGQLVDIA CKVCQAYLGQ LEHEDIDTSA DAVEDLTEAE
WEDLTQQYYS LVHGDAFISN SRNYFSQCQA LLNRITSVNP QTDIDGLRNI WIIKPAAKSR
GRDIVCMDRV EEILELAAAD HPLSRDNKWV VQKYIETPLL ICDTKFDIRQ WFLVTDWNPL
TIWFYKESYL RFSTQRFSLD KLDSAIHLCN NAVQKYLKND VGRSPLLPAH NMWTSTRFQE
YLQRQGRGAV WGSVIYPSMK KAIAHAMKVA QDHVEPRKNS FELYGADFVL GRDFRPWLIE
INSSPTMHPS TPVTAQLCAQ VQEDTIKVAV DRSCDIGNFE LLWRQPVVEP PPFSGSDLCV
AGVSVRRARR QVLPVCNLKA SASLLDAQPL KARGPSAMPD PAQGPPSPAL QRDLGLKEEK
GLPLALLAPL RGAAESGGAA QPTRTKAAGK VELPACPCRH VDSQAPNTGV PVAQPAKSWD
PNQLNAHPLE PVLRGLKTAE GALRPPPGGK GEGTVCSRLP HHGHHVAACQ TTGTTWDGGP
GVCFLRQLLA SELPMGPGLP RDPRAPPCLV CRGLLPPAGP CKRCRSFCAA VLQGASFVRL
GGRSCSPRTP
