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Protein

Protein timeless homolog

Gene

TIMELESS

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication and in the regulation of the circadian clock. Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock. Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. Forms a complex with TIPIN and this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. Timeless promotes TIPIN nuclear localization. Involved in cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. May also play an important role in epithelial cell morphogenesis and formation of branching tubules.4 Publications

GO - Biological processi

  • branching morphogenesis of an epithelial tube Source: Ensembl
  • cell cycle phase transition Source: BHF-UCL
  • cell division Source: UniProtKB-KW
  • cellular response to bleomycin Source: UniProtKB
  • cellular response to cisplatin Source: UniProtKB
  • cellular response to DNA damage stimulus Source: UniProtKB
  • cellular response to hydroxyurea Source: UniProtKB
  • circadian rhythm Source: UniProtKB
  • detection of abiotic stimulus Source: ProtInc
  • DNA replication Source: Reactome
  • lung development Source: Ensembl
  • mitotic nuclear division Source: UniProtKB-KW
  • morphogenesis of an epithelium Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: Ensembl
  • positive regulation of double-strand break repair Source: UniProtKB
  • regulation of circadian rhythm Source: UniProtKB
  • response to abiotic stimulus Source: ProtInc
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Biological rhythms, Cell cycle, Cell division, DNA damage, Mitosis, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-5693607. Processing of DNA double-strand break ends.

Names & Taxonomyi

Protein namesi
Recommended name:
Protein timeless homolog
Short name:
hTIM
Gene namesi
Name:TIMELESSImported
Synonyms:TIM1 Publication, TIM11 Publication, TIMELESS11 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:11813. TIMELESS.

Subcellular locationi

  • Nucleus 1 Publication

GO - Cellular componenti

  • microtubule cytoskeleton Source: HPA
  • nuclear chromatin Source: HGNC
  • nucleolus Source: HPA
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Organism-specific databases

DisGeNETi8914.
OpenTargetsiENSG00000111602.
PharmGKBiPA36520.

Polymorphism and mutation databases

BioMutaiTIMELESS.
DMDMi296452931.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000725381 – 1208Protein timeless homologAdd BLAST1208

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei281PhosphoserineCombined sources1
Modified residuei1074PhosphoserineCombined sources1
Modified residuei1087PhosphoserineCombined sources1
Modified residuei1089PhosphothreonineCombined sources1
Modified residuei1149PhosphoserineCombined sources1
Modified residuei1173PhosphoserineCombined sources1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ9UNS1.
PaxDbiQ9UNS1.
PeptideAtlasiQ9UNS1.
PRIDEiQ9UNS1.

PTM databases

iPTMnetiQ9UNS1.
PhosphoSitePlusiQ9UNS1.

Expressioni

Tissue specificityi

Expressed in all tissues examined including brain, heart, lung, liver, skeletal muscle, kidney, placenta, pancreas, spleen, thymus and testis. Highest levels of expression in placenta, pancreas, thymus and testis.2 Publications

Inductioni

Regulated by the cell cycle. High levels in S, G2 and M phases, with highest level in S phase. Low expression in G0 and G1 phases.1 Publication

Gene expression databases

BgeeiENSG00000111602.
CleanExiHS_TIMELESS.
GenevisibleiQ9UNS1. HS.

Organism-specific databases

HPAiHPA034792.
HPA060655.

Interactioni

Subunit structurei

Homodimer or homomultimer (By similarity). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSKN1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts directly with PER2; the interaction with PER2 is via its second PAS domain. Interacts directly with PER1 and PER3 (By similarity). Interacts with CRY2, CHEK1, ATR and ATRIP (PubMed:15798197). Interacts with CRY1 (By similarity). Interacts with CLSPN (PubMed:17141802). Interacts with TIPIN (PubMed:17116885, PubMed:17102137, PubMed:17296725). Interacts with DDX11; this interaction increases recruitment of both proteins onto chromatin in response to replication stress induction by hydroxyurea (PubMed:20124417).By similarity7 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CHEK1O147572EBI-2212315,EBI-974488

Protein-protein interaction databases

BioGridi114428. 33 interactors.
DIPiDIP-47395N.
IntActiQ9UNS1. 13 interactors.
STRINGi9606.ENSP00000450607.

Structurei

Secondary structure

11208
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi1008 – 1012Combined sources5
Helixi1016 – 1033Combined sources18
Beta strandi1042 – 1044Combined sources3
Helixi1049 – 1055Combined sources7
Helixi1058 – 1067Combined sources10
Turni1074 – 1076Combined sources3
Beta strandi1078 – 1082Combined sources5
Helixi1088 – 1096Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4XHTX-ray1.65A/B/C/D1000-1098[»]
4XHUX-ray2.09B/D1000-1098[»]
4XHWX-ray2.85A/B/C/D1000-1098[»]
ProteinModelPortaliQ9UNS1.
SMRiQ9UNS1.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 309Required for homodimerization and for interaction with CRY1 and CHEK1By similarityAdd BLAST309
Regioni1082 – 1208Required for nuclear localizationBy similarityAdd BLAST127

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi661 – 688Glu-richAdd BLAST28

Sequence similaritiesi

Belongs to the timeless family.Curated

Phylogenomic databases

eggNOGiKOG1974. Eukaryota.
ENOG410XQM6. LUCA.
GeneTreeiENSGT00390000015124.
HOGENOMiHOG000133002.
HOVERGENiHBG079258.
InParanoidiQ9UNS1.
KOiK03155.
OMAiRKGTQIV.
OrthoDBiEOG091G00YS.
PhylomeDBiQ9UNS1.
TreeFamiTF312802.

Family and domain databases

InterProiIPR006906. Timeless.
IPR007725. TIMELESS_C.
[Graphical view]
PfamiPF04821. TIMELESS. 1 hit.
PF05029. TIMELESS_C. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 12 Publications (identifier: Q9UNS1-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MDLHMMNCEL LATCSALGYL EGDTYHKEPD CLESVKDLIR YLRHEDETRD
60 70 80 90 100
VRQQLGAAQI LQSDLLPILT QHHQDKPLFD AVIRLMVNLT QPALLCFGNL
110 120 130 140 150
PKEPSFRHHF LQVLTYLQAY KEAFASEKAF GVLSETLYEL LQLGWEERQE
160 170 180 190 200
EDNLLIERIL LLVRNILHVP ADLDQEKKID DDASAHDQLL WAIHLSGLDD
210 220 230 240 250
LLLFLASSSA EEQWSLHVLE IVSLMFRDQN PEQLAGVGQG RLAQERSADF
260 270 280 290 300
AELEVLRQRE MAEKKTRALQ RGNRHSRFGG SYIVQGLKSI GERDLIFHKG
310 320 330 340 350
LHNLRNYSSD LGKQPKKVPK RRQAARELSI QRRSALNVRL FLRDFCSEFL
360 370 380 390 400
ENCYNRLMGS VKDHLLREKA QQHDETYYMW ALAFFMAFNR AASFRPGLVS
410 420 430 440 450
ETLSVRTFHF IEQNLTNYYE MMLTDRKEAA SWARRMHLAL KAYQELLATV
460 470 480 490 500
NEMDISPDEA VRESSRIIKN NIFYVMEYRE LFLALFRKFD ERCQPRSFLR
510 520 530 540 550
DLVETTHLFL KMLERFCRSR GNLVVQNKQK KRRKKKKKVL DQAIVSGNVP
560 570 580 590 600
SSPEEVEAVW PALAEQLQCC AQNSELSMDS VVPFDAASEV PVEEQRAEAM
610 620 630 640 650
VRIQDCLLAG QAPQALTLLR SAREVWPEGD VFGSQDISPE EEIQLLKQIL
660 670 680 690 700
SAPLPRQQGP EERGAEEEEE EEEEEEEELQ VVQVSEKEFN FLDYLKRFAC
710 720 730 740 750
STVVRAYVLL LRSYQQNSAH TNHCIVKMLH RLAHDLKMEA LLFQLSVFCL
760 770 780 790 800
FNRLLSDPAA GAYKELVTFA KYILGKFFAL AAVNQKAFVE LLFWKNTAVV
810 820 830 840 850
REMTEGYGSL DDRSSSRRAP TWSPEEEAHL RELYLANKDV EGQDVVEAIL
860 870 880 890 900
AHLNTVPRTR KQIIHHLVQM GLADSVKDFQ RKGTHIVLWT GDQELELQRL
910 920 930 940 950
FEEFRDSDDV LGHIMKNITA KRSRARIVDK LLALGLVAER RELYKKRQKK
960 970 980 990 1000
LASSILPNGA ESLKDFCQED LEEEENLPEE DSEEEEEGGS EAEQVQGSLV
1010 1020 1030 1040 1050
LSNENLGQSL HQEGFSIPLL WLQNCLIRAA DDREEDGCSQ AVPLVPLTEE
1060 1070 1080 1090 1100
NEEAMENEQF QQLLRKLGVR PPASGQETFW RIPAKLSPTQ LRRAAASLSQ
1110 1120 1130 1140 1150
PEEEQKLQPE LQPKVPGEQG SDEEHCKEHR AQALRALLLA HKKKAGLASP
1160 1170 1180 1190 1200
EEEDAVGKEP LKAAPKKRQL LDSDEEQEED EGRNRAPELG APGIQKKKRY

QIEDDEDD
Length:1,208
Mass (Da):138,658
Last modified:May 18, 2010 - v2
Checksum:i16C6C07DDC6D2701
GO
Isoform 21 Publication (identifier: Q9UNS1-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     177-177: Missing.

Show »
Length:1,207
Mass (Da):138,530
Checksum:iC116D7FF6F29B326
GO

Sequence cautioni

The sequence AAH39842 differs from that shown. Contaminating sequence. Potential poly-A sequence.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_047879129A → S.1 PublicationCorresponds to variant rs72478986dbSNPEnsembl.1
Natural variantiVAR_036435429A → D in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_021483455I → L.3 PublicationsCorresponds to variant rs774027dbSNPEnsembl.1
Natural variantiVAR_047880471N → S.1 PublicationCorresponds to variant rs72478993dbSNPEnsembl.1
Natural variantiVAR_021484831R → Q.3 PublicationsCorresponds to variant rs774047dbSNPEnsembl.1
Natural variantiVAR_047881870M → V.1 PublicationCorresponds to variant rs61733875dbSNPEnsembl.1
Natural variantiVAR_047882922R → H.1 PublicationCorresponds to variant rs72478999dbSNPEnsembl.1
Natural variantiVAR_047883924R → W.1 PublicationCorresponds to variant rs72479000dbSNPEnsembl.1
Natural variantiVAR_0364361008Q → E in a breast cancer sample; somatic mutation. 1 PublicationCorresponds to variant rs151188513dbSNPEnsembl.1
Natural variantiVAR_0478841017I → T.1 PublicationCorresponds to variant rs61376834dbSNPEnsembl.1
Natural variantiVAR_0214851018P → L.2 PublicationsCorresponds to variant rs2291739dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_051693177Missing in isoform 2. 2 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB015597 mRNA. Translation: BAA36499.1.
AF098162 mRNA. Translation: AAC80011.1.
EU627094 Genomic DNA. Translation: ACD11488.1.
AC024884 Genomic DNA. No translation available.
BC039842 mRNA. Translation: AAH39842.1. Sequence problems.
BC050557 mRNA. Translation: AAH50557.1.
CCDSiCCDS81699.1. [Q9UNS1-2]
CCDS8918.1. [Q9UNS1-1]
RefSeqiNP_001317224.1. NM_001330295.1.
NP_003911.2. NM_003920.4. [Q9UNS1-1]
UniGeneiHs.118631.

Genome annotation databases

EnsembliENST00000229201; ENSP00000229201; ENSG00000111602. [Q9UNS1-2]
ENST00000553532; ENSP00000450607; ENSG00000111602. [Q9UNS1-1]
GeneIDi8914.
KEGGihsa:8914.
UCSCiuc001slf.3. human. [Q9UNS1-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB015597 mRNA. Translation: BAA36499.1.
AF098162 mRNA. Translation: AAC80011.1.
EU627094 Genomic DNA. Translation: ACD11488.1.
AC024884 Genomic DNA. No translation available.
BC039842 mRNA. Translation: AAH39842.1. Sequence problems.
BC050557 mRNA. Translation: AAH50557.1.
CCDSiCCDS81699.1. [Q9UNS1-2]
CCDS8918.1. [Q9UNS1-1]
RefSeqiNP_001317224.1. NM_001330295.1.
NP_003911.2. NM_003920.4. [Q9UNS1-1]
UniGeneiHs.118631.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4XHTX-ray1.65A/B/C/D1000-1098[»]
4XHUX-ray2.09B/D1000-1098[»]
4XHWX-ray2.85A/B/C/D1000-1098[»]
ProteinModelPortaliQ9UNS1.
SMRiQ9UNS1.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114428. 33 interactors.
DIPiDIP-47395N.
IntActiQ9UNS1. 13 interactors.
STRINGi9606.ENSP00000450607.

PTM databases

iPTMnetiQ9UNS1.
PhosphoSitePlusiQ9UNS1.

Polymorphism and mutation databases

BioMutaiTIMELESS.
DMDMi296452931.

Proteomic databases

EPDiQ9UNS1.
PaxDbiQ9UNS1.
PeptideAtlasiQ9UNS1.
PRIDEiQ9UNS1.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000229201; ENSP00000229201; ENSG00000111602. [Q9UNS1-2]
ENST00000553532; ENSP00000450607; ENSG00000111602. [Q9UNS1-1]
GeneIDi8914.
KEGGihsa:8914.
UCSCiuc001slf.3. human. [Q9UNS1-1]

Organism-specific databases

CTDi8914.
DisGeNETi8914.
GeneCardsiTIMELESS.
H-InvDBHIX0010725.
HGNCiHGNC:11813. TIMELESS.
HPAiHPA034792.
HPA060655.
MIMi603887. gene.
neXtProtiNX_Q9UNS1.
OpenTargetsiENSG00000111602.
PharmGKBiPA36520.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1974. Eukaryota.
ENOG410XQM6. LUCA.
GeneTreeiENSGT00390000015124.
HOGENOMiHOG000133002.
HOVERGENiHBG079258.
InParanoidiQ9UNS1.
KOiK03155.
OMAiRKGTQIV.
OrthoDBiEOG091G00YS.
PhylomeDBiQ9UNS1.
TreeFamiTF312802.

Enzyme and pathway databases

ReactomeiR-HSA-5693607. Processing of DNA double-strand break ends.

Miscellaneous databases

ChiTaRSiTIMELESS. human.
GenomeRNAii8914.
PROiQ9UNS1.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000111602.
CleanExiHS_TIMELESS.
GenevisibleiQ9UNS1. HS.

Family and domain databases

InterProiIPR006906. Timeless.
IPR007725. TIMELESS_C.
[Graphical view]
PfamiPF04821. TIMELESS. 1 hit.
PF05029. TIMELESS_C. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTIM_HUMAN
AccessioniPrimary (citable) accession number: Q9UNS1
Secondary accession number(s): B2ZAV0
, O94802, Q86VM1, Q8IWH3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 15, 2005
Last sequence update: May 18, 2010
Last modified: November 30, 2016
This is version 139 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.