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Protein

Protein timeless homolog

Gene

TIMELESS

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 - Molecular functioni

  • DNA binding Source: GO_Central
  • protein heterodimerization activity Source: Ensembl
  • protein homodimerization activity Source: Ensembl

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein
Biological processBiological 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

EuPathDBiHostDB:ENSG00000111602.11
HGNCiHGNC:11813 TIMELESS
MIMi603887 gene
neXtProtiNX_Q9UNS1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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
ProteomicsDBi85326
85327 [Q9UNS1-2]

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 Expressed in 163 organ(s), highest expression level in embryo
CleanExiHS_TIMELESS
GenevisibleiQ9UNS1 HS

Organism-specific databases

HPAiHPA060655

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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114428, 77 interactors
DIPiDIP-47395N
IntActiQ9UNS1, 14 interactors
MINTiQ9UNS1
STRINGi9606.ENSP00000450607

Structurei

Secondary structure

11208
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

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
OMAiDSMVPFD
OrthoDBiEOG091G00YS
PhylomeDBiQ9UNS1
TreeFamiTF312802

Family and domain databases

InterProiView protein in InterPro
IPR006906 Timeless
IPR007725 TIMELESS_C
PfamiView protein in Pfam
PF04821 TIMELESS, 1 hit
PF05029 TIMELESS_C, 1 hit

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 → S1 PublicationCorresponds to variant dbSNP:rs72478986Ensembl.1
Natural variantiVAR_036435429A → D in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_021483455I → L3 PublicationsCorresponds to variant dbSNP:rs774027Ensembl.1
Natural variantiVAR_047880471N → S1 PublicationCorresponds to variant dbSNP:rs72478993Ensembl.1
Natural variantiVAR_021484831R → Q3 PublicationsCorresponds to variant dbSNP:rs774047Ensembl.1
Natural variantiVAR_047881870M → V1 PublicationCorresponds to variant dbSNP:rs61733875Ensembl.1
Natural variantiVAR_047882922R → H1 PublicationCorresponds to variant dbSNP:rs72478999Ensembl.1
Natural variantiVAR_047883924R → W1 PublicationCorresponds to variant dbSNP:rs72479000Ensembl.1
Natural variantiVAR_0364361008Q → E in a breast cancer sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs151188513Ensembl.1
Natural variantiVAR_0478841017I → T1 PublicationCorresponds to variant dbSNP:rs61376834Ensembl.1
Natural variantiVAR_0214851018P → L2 PublicationsCorresponds to variant dbSNP:rs2291739Ensembl.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 [Q9UNS1-2]
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

Similar proteinsi

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 [Q9UNS1-2]
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[»]
5MQIX-ray1.85A1-238[»]
A331-463[»]
ProteinModelPortaliQ9UNS1
SMRiQ9UNS1
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114428, 77 interactors
DIPiDIP-47395N
IntActiQ9UNS1, 14 interactors
MINTiQ9UNS1
STRINGi9606.ENSP00000450607

PTM databases

iPTMnetiQ9UNS1
PhosphoSitePlusiQ9UNS1

Polymorphism and mutation databases

BioMutaiTIMELESS
DMDMi296452931

Proteomic databases

EPDiQ9UNS1
PaxDbiQ9UNS1
PeptideAtlasiQ9UNS1
PRIDEiQ9UNS1
ProteomicsDBi85326
85327 [Q9UNS1-2]

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
EuPathDBiHostDB:ENSG00000111602.11
GeneCardsiTIMELESS
H-InvDBiHIX0010725
HGNCiHGNC:11813 TIMELESS
HPAiHPA060655
MIMi603887 gene
neXtProtiNX_Q9UNS1
OpenTargetsiENSG00000111602
PharmGKBiPA36520
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

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

Miscellaneous databases

ChiTaRSiTIMELESS human
GenomeRNAii8914
PROiPR:Q9UNS1
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000111602 Expressed in 163 organ(s), highest expression level in embryo
CleanExiHS_TIMELESS
GenevisibleiQ9UNS1 HS

Family and domain databases

InterProiView protein in InterPro
IPR006906 Timeless
IPR007725 TIMELESS_C
PfamiView protein in Pfam
PF04821 TIMELESS, 1 hit
PF05029 TIMELESS_C, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiTIM_HUMAN
AccessioniPrimary (citable) accession number: Q9UNS1
Secondary accession number(s): B2ZAV0
, O94802, Q86VM1, Q8IWH3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 15, 2005
Last sequence update: May 18, 2010
Last modified: November 7, 2018
This is version 156 of the entry and version 2 of the sequence. See 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. SIMILARITY comments
    Index of protein domains and families
  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. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
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