Reviewed, UniProtKB/Swiss-Prot Q9UNS1 (TIM_HUMAN)

Names and origin

Protein names

Recommended name:
    Protein timeless homolog
      Short name=hTIM

Gene names

Name:	TIMELESS
Synonyms:	TIM, TIM1, TIMELESS1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1208 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Required for normal progression of S-phase. Involved in the circadian rhythm autoregulatory loop. Negatively regulates CLOCK-NPAS2/BMAL1-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. Promotes TIPIN nuclear localiZation. Involved in cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHK1 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. Ref.2 Ref.11 Ref.13
Subunit structure	Homomultimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSKN1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts directly with PER1, PER2 and PER3. Interacts with PER2 via its second PAS domain in vitro. Binds CRY1, CRY2, CHK1, ATR and ATRIP By similarity. Interacts with TIPIN and CLSPN.
Subcellular location	Nucleus. Ref.11
Tissue specificity	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. Ref.2 Ref.1
Induction	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. Ref.6
Sequence similarities	Belongs to the timeless family.
Sequence caution	The sequence AAH39842.1 differs from that shown. Reason: Miscellaneous discrepancy. Contaminating sequence. Potential poly-A sequence.

Ontologies

Keywords
Biological process	Biological rhythms Cell cycle Cell division DNA damage Mitosis Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Molecular function	Developmental protein
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	cell division Inferred from electronic annotation. Source: UniProtKB-KW circadian rhythm Ref.2 Inferred from sequence or structural similarity. Source: UniProtKB detection of abiotic stimulus Traceable author statement. Source: ProtInc mitosis Inferred from electronic annotation. Source: UniProtKB-KW morphogenesis of an epithelium Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of transcription Ref.2 Inferred from direct assay. Source: UniProtKB regulation of S phase Ref.10 Inferred from mutant phenotype. Source: HGNC response to DNA damage stimulus Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nuclear chromatin Ref.10 Inferred from direct assay. Source: HGNC
Molecular function	protein binding Ref.6 Ref.10 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CHEK1	O14757	2	EBI-2212315,EBI-974488
CRY2	Q49AN0	1	EBI-2212315,EBI-2212355

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 Ref.2 Ref.1 (identifier: Q9UNS1-1)

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.

Isoform 2 Ref.2 (identifier: Q9UNS1-2)

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1208	1208	Protein timeless homolog		PRO_0000072538
Regions
	Compositional bias	661 – 688	28	Glu-rich
Amino acid modifications
	Modified residue	299	1	N6-acetyllysine Ref.17
	Modified residue	1089	1	Phosphothreonine Ref.12
	Modified residue	1173	1	Phosphoserine Ref.5 Ref.7 Ref.8 Ref.14 Ref.15
Natural variations
	Alternative sequence	177	1	Missing in isoform 2. Ref.2		VSP_051693
	Natural variant	129	1	A → S		VAR_047879
	Natural variant	429	1	A → D in a breast cancer sample; somatic mutation. Ref.18		VAR_036435
	Natural variant	455	1	L → I: dbSNP rs774027. Ref.2 Ref.3 Ref.4		VAR_021483
	Natural variant	471	1	N → S		VAR_047880
	Natural variant	831	1	Q → R: dbSNP rs774047. Ref.2 Ref.3 Ref.4		VAR_021484
	Natural variant	870	1	M → V		VAR_047881
	Natural variant	922	1	R → H		VAR_047882
	Natural variant	924	1	R → W		VAR_047883
	Natural variant	1008	1	Q → E in a breast cancer sample; somatic mutation. Ref.18		VAR_036436
	Natural variant	1017	1	I → T		VAR_047884
	Natural variant	1018	1	P → L: dbSNP rs2291739. Ref.3 Ref.4		VAR_021485

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: 5456F814CAB62F8E	FASTA	1,208	138,630
	10 20 30 40 50 60 MDLHMMNCEL LATCSALGYL EGDTYHKEPD CLESVKDLIR YLRHEDETRD VRQQLGAAQI 70 80 90 100 110 120 LQSDLLPILT QHHQDKPLFD AVIRLMVNLT QPALLCFGNL PKEPSFRHHF LQVLTYLQAY 130 140 150 160 170 180 KEAFASEKAF GVLSETLYEL LQLGWEERQE EDNLLIERIL LLVRNILHVP ADLDQEKKID 190 200 210 220 230 240 DDASAHDQLL WAIHLSGLDD LLLFLASSSA EEQWSLHVLE IVSLMFRDQN PEQLAGVGQG 250 260 270 280 290 300 RLAQERSADF AELEVLRQRE MAEKKTRALQ RGNRHSRFGG SYIVQGLKSI GERDLIFHKG 310 320 330 340 350 360 LHNLRNYSSD LGKQPKKVPK RRQAARELSI QRRSALNVRL FLRDFCSEFL ENCYNRLMGS 370 380 390 400 410 420 VKDHLLREKA QQHDETYYMW ALAFFMAFNR AASFRPGLVS ETLSVRTFHF IEQNLTNYYE 430 440 450 460 470 480 MMLTDRKEAA SWARRMHLAL KAYQELLATV NEMDLSPDEA VRESSRIIKN NIFYVMEYRE 490 500 510 520 530 540 LFLALFRKFD ERCQPRSFLR DLVETTHLFL KMLERFCRSR GNLVVQNKQK KRRKKKKKVL 550 560 570 580 590 600 DQAIVSGNVP SSPEEVEAVW PALAEQLQCC AQNSELSMDS VVPFDAASEV PVEEQRAEAM 610 620 630 640 650 660 VRIQDCLLAG QAPQALTLLR SAREVWPEGD VFGSQDISPE EEIQLLKQIL SAPLPRQQGP 670 680 690 700 710 720 EERGAEEEEE EEEEEEEELQ VVQVSEKEFN FLDYLKRFAC STVVRAYVLL LRSYQQNSAH 730 740 750 760 770 780 TNHCIVKMLH RLAHDLKMEA LLFQLSVFCL FNRLLSDPAA GAYKELVTFA KYILGKFFAL 790 800 810 820 830 840 AAVNQKAFVE LLFWKNTAVV REMTEGYGSL DDRSSSRRAP TWSPEEEAHL QELYLANKDV 850 860 870 880 890 900 EGQDVVEAIL AHLNTVPRTR KQIIHHLVQM GLADSVKDFQ RKGTHIVLWT GDQELELQRL 910 920 930 940 950 960 FEEFRDSDDV LGHIMKNITA KRSRARIVDK LLALGLVAER RELYKKRQKK LASSILPNGA 970 980 990 1000 1010 1020 ESLKDFCQED LEEEENLPEE DSEEEEEGGS EAEQVQGSLV LSNENLGQSL HQEGFSIPLL 1030 1040 1050 1060 1070 1080 WLQNCLIRAA DDREEDGCSQ AVPLVPLTEE NEEAMENEQF QQLLRKLGVR PPASGQETFW 1090 1100 1110 1120 1130 1140 RIPAKLSPTQ LRRAAASLSQ PEEEQKLQPE LQPKVPGEQG SDEEHCKEHR AQALRALLLA 1150 1160 1170 1180 1190 1200 HKKKAGLASP EEEDAVGKEP LKAAPKKRQL LDSDEEQEED EGRNRAPELG APGIQKKKRY QIEDDEDD
	Isoform 2. Checksum: 8386EF9679F2BBA9	FASTA	1,207	138,502
	10 20 30 40 50 60 MDLHMMNCEL LATCSALGYL EGDTYHKEPD CLESVKDLIR YLRHEDETRD VRQQLGAAQI 70 80 90 100 110 120 LQSDLLPILT QHHQDKPLFD AVIRLMVNLT QPALLCFGNL PKEPSFRHHF LQVLTYLQAY 130 140 150 160 170 180 KEAFASEKAF GVLSETLYEL LQLGWEERQE EDNLLIERIL LLVRNILHVP ADLDQEKIDD 190 200 210 220 230 240 DASAHDQLLW AIHLSGLDDL LLFLASSSAE EQWSLHVLEI VSLMFRDQNP EQLAGVGQGR 250 260 270 280 290 300 LAQERSADFA ELEVLRQREM AEKKTRALQR GNRHSRFGGS YIVQGLKSIG ERDLIFHKGL 310 320 330 340 350 360 HNLRNYSSDL GKQPKKVPKR RQAARELSIQ RRSALNVRLF LRDFCSEFLE NCYNRLMGSV 370 380 390 400 410 420 KDHLLREKAQ QHDETYYMWA LAFFMAFNRA ASFRPGLVSE TLSVRTFHFI EQNLTNYYEM 430 440 450 460 470 480 MLTDRKEAAS WARRMHLALK AYQELLATVN EMDLSPDEAV RESSRIIKNN IFYVMEYREL 490 500 510 520 530 540 FLALFRKFDE RCQPRSFLRD LVETTHLFLK MLERFCRSRG NLVVQNKQKK RRKKKKKVLD 550 560 570 580 590 600 QAIVSGNVPS SPEEVEAVWP ALAEQLQCCA QNSELSMDSV VPFDAASEVP VEEQRAEAMV 610 620 630 640 650 660 RIQDCLLAGQ APQALTLLRS AREVWPEGDV FGSQDISPEE EIQLLKQILS APLPRQQGPE 670 680 690 700 710 720 ERGAEEEEEE EEEEEEELQV VQVSEKEFNF LDYLKRFACS TVVRAYVLLL RSYQQNSAHT 730 740 750 760 770 780 NHCIVKMLHR LAHDLKMEAL LFQLSVFCLF NRLLSDPAAG AYKELVTFAK YILGKFFALA 790 800 810 820 830 840 AVNQKAFVEL LFWKNTAVVR EMTEGYGSLD DRSSSRRAPT WSPEEEAHLQ ELYLANKDVE 850 860 870 880 890 900 GQDVVEAILA HLNTVPRTRK QIIHHLVQMG LADSVKDFQR KGTHIVLWTG DQELELQRLF 910 920 930 940 950 960 EEFRDSDDVL GHIMKNITAK RSRARIVDKL LALGLVAERR ELYKKRQKKL ASSILPNGAE 970 980 990 1000 1010 1020 SLKDFCQEDL EEEENLPEED SEEEEEGGSE AEQVQGSLVL SNENLGQSLH QEGFSIPLLW 1030 1040 1050 1060 1070 1080 LQNCLIRAAD DREEDGCSQA VPLVPLTEEN EEAMENEQFQ QLLRKLGVRP PASGQETFWR 1090 1100 1110 1120 1130 1140 IPAKLSPTQL RRAAASLSQP EEEQKLQPEL QPKVPGEQGS DEEHCKEHRA QALRALLLAH 1150 1160 1170 1180 1190 1200 KKKAGLASPE EEDAVGKEPL KAAPKKRQLL DSDEEQEEDE GRNRAPELGA PGIQKKKRYQ IEDDEDD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of the mammalian homologues of the Drosophila timeless gene, Timeless1." Koike N., Hida A., Numano R., Hirose M., Sakaki Y., Tei H. FEBS Lett. 441:427-431(1998) [PubMed: 9891984] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY. Tissue: Brain.
[2]	"Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription." Sangoram A.M., Saez L., Antoch M.P., Gekakis N., Staknis D., Whiteley A., Fruechte E.M., Vitaterna M.H., Shimomura K., King D.P., Young M.W., Weitz C.J., Takahashi J.S. Neuron 21:1101-1113(1998) [PubMed: 9856465] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, TISSUE SPECIFICITY, VARIANTS ILE-455 AND ARG-831. Tissue: Placenta.
[3]	NIEHS SNPs program Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS SER-129; ILE-455; SER-471; ARG-831; VAL-870; HIS-922; TRP-924; THR-1017 AND LEU-1018.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), VARIANTS ILE-455; ARG-831 AND LEU-1018. Tissue: Duodenum and Skin.
[5]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, MASS SPECTROMETRY. Tissue: Epithelium.
[6]	"Coupling of human circadian and cell cycles by the timeless protein." Uensal-Kacmaz K., Mullen T.E., Kaufmann W.K., Sancar A. Mol. Cell. Biol. 25:3109-3116(2005) [PubMed: 15798197] [Abstract] Cited for: INTERACTION WITH ATR; ATRIP; CHK1 AND CRY2, INDUCTION.
[7]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, MASS SPECTROMETRY. Tissue: Epithelium.
[8]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed: 16964243] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, MASS SPECTROMETRY. Tissue: Epithelium.
[9]	"Tipin and Timeless form a mutually protective complex required for genotoxic stress resistance and checkpoint function." Chou D.M., Elledge S.J. Proc. Natl. Acad. Sci. U.S.A. 103:18143-18147(2006) [PubMed: 17116885] [Abstract] Cited for: INTERACTION WITH TIPIN.
[10]	"Human Tim/Timeless-interacting protein, Tipin, is required for efficient progression of S phase and DNA replication checkpoint." Yoshizawa-Sugata N., Masai H. J. Biol. Chem. 282:2729-2740(2007) [PubMed: 17102137] [Abstract] Cited for: INTERACTION WITH TIPIN.
[11]	"Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors." Gotter A.L., Suppa C., Emanuel B.S. J. Mol. Biol. 366:36-52(2007) [PubMed: 17141802] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH CLSPN, FUNCTION.
[12]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1089, MASS SPECTROMETRY. Tissue: Epithelium.
[13]	"The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement." Uensal-Kacmaz K., Chastain P.D., Qu P.-P., Minoo P., Cordeiro-Stone M., Sancar A., Kaufmann W.K. Mol. Cell. Biol. 27:3131-3142(2007) [PubMed: 17296725] [Abstract] Cited for: INTERACTION WITH TIPIN, FUNCTION.
[14]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, MASS SPECTROMETRY.
[15]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, MASS SPECTROMETRY.
[16]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[17]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-299, MASS SPECTROMETRY.
[18]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASP-429 AND GLU-1008.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	AB015597 mRNA. Translation: BAA36499.1. AF098162 mRNA. Translation: AAC80011.1. EU627094 Genomic DNA. Translation: ACD11488.1. BC039842 mRNA. Translation: AAH39842.1. Sequence problems. BC050557 mRNA. Translation: AAH50557.1.
IPI	IPI00335541. IPI00554678.
RefSeq	NP_003911.2.
UniGene	Hs.118631
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9UNS1. 4 interactions.
STRING	Q9UNS1.
PTM databases
PhosphoSite	Q9UNS1.
Proteomic databases
PRIDE	Q9UNS1.
Genome annotation databases
Ensembl	ENST00000229201; ENSP00000229201; ENSG00000111602; Homo sapiens. [Genome view] ENST00000447258; ENSP00000400915; ENSG00000111602; Homo sapiens. [Genome view] ENST00000452204; ENSP00000403797; ENSG00000111602; Homo sapiens. [Genome view]
GeneID	8914.
KEGG	hsa:8914.
UCSC	uc001slf.1. human.
Organism-specific databases
CTD	8914.
GeneCards	GC12M055097.
H-InvDB	HIX0010725.
HGNC	HGNC:11813. TIMELESS.
MIM	603887. gene.
PharmGKB	PA36520.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q9UNS1.
HOVERGEN	Q9UNS1.
Enzyme and pathway databases
Pathway_Interaction_DB	circadianpathway. Circadian rhythm pathway.
Gene expression databases
ArrayExpress	Q9UNS1.
Bgee	Q9UNS1.
CleanEx	HS_TIMELESS.
Genevestigator	Q9UNS1.
GermOnline	ENSG00000111602. Homo sapiens.
Family and domain databases
InterPro	IPR006906. Timeless. IPR007725. TIMELESS_C. [Graphical view]
Pfam	PF04821. TIMELESS. 1 hit. PF05029. TIMELESS_C. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	33532.
SOURCE	Search...

Entry information

Entry name

TIM_HUMAN

Accession

Primary (citable) accession number: Q9UNS1
Secondary accession number(s): B2ZAV0 , O94802, Q86VM1, Q8IWH3

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 15, 2005
Last sequence update:	May 1, 2000
Last modified:	October 13, 2009
This is version 69 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.