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Protein

Denticleless protein homolog

Gene

Dtl

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis. The DCX(DTL) complex, also named CRL4(CDT2) complex, mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBXO18/FBH1, KMT5A and SDE2. CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication. CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing. KMT5A degradation is also important for a proper regulation of mechanisms such as TGF-beta signaling, cell cycle progression, DNA repair and cell migration. Most substrates require their interaction with PCNA for their polyubiquitination: substrates interact with PCNA via their PIP-box, and those containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to their degradation. In undamaged proliferating cells, the DCX(DTL) complex also promotes the 'Lys-164' monoubiquitination of PCNA, thereby being involved in PCNA-dependent translesion DNA synthesis.By similarity

Caution

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processDNA damage, DNA replication, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-MMU-110314 Recognition of DNA damage by PCNA-containing replication complex
R-MMU-8951664 Neddylation
UniPathwayiUPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
Denticleless protein homolog
Alternative name(s):
Lethal(2) denticleless protein homolog
Meth A retinoic acid-regulated nuclear matrix-associated protein
Short name:
Meth A RAMP
Retinoic acid-regulated nuclear matrix-associated protein
Gene namesi
Name:Dtl
Synonyms:Cdt2, L2dtl, Ramp
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 1

Organism-specific databases

MGIiMGI:1924093 Dtl

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

Chromosome, Cytoplasm, Cytoskeleton, Membrane, Nucleus

Pathology & Biotechi

Disruption phenotypei

Early embryonic lethality due to cell cycle progression failure, termination of cell division, and, eventually, embryonic death during the preimplantation stage.1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002748681 – 729Denticleless protein homologAdd BLAST729

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineBy similarity1
Modified residuei196PhosphothreonineBy similarity1
Modified residuei409PhosphoserineBy similarity1
Modified residuei425PhosphoserineBy similarity1
Modified residuei463Phosphothreonine; by CDK1 and CDK2By similarity1
Modified residuei484PhosphoserineBy similarity1
Modified residuei489PhosphoserineBy similarity1
Modified residuei494PhosphoserineBy similarity1
Modified residuei511PhosphoserineCombined sources1
Modified residuei515PhosphothreonineCombined sources1
Modified residuei556PhosphoserineBy similarity1
Modified residuei675PhosphoserineBy similarity1
Modified residuei678PhosphoserineBy similarity1
Modified residuei683PhosphothreonineBy similarity1
Modified residuei701PhosphothreonineCombined sources1

Post-translational modificationi

Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C). Autoubiquitinated through 'Lys-48'-polyubiquitin chains in a PCNA-independent reaction, allowing proteasomal turnover. Polyubiquitinated by SCF(FBXO11) when not phosphorylated, leading to its degradation. A tight regulation of the polyubiquitination by SCF(FBXO11) is involved in the control of different processes such as TGF-beta signaling, cell cycle progression and exit (By similarity).By similarity
Phosphorylated at Thr-463 by CDK1/Cyclin B and CDK2/Cycnlin A but not by CDK2/Cyclin E, MAPK1 or PLK1. Phosphorylation at Thr-463 inhibits the interaction with FBXO11 and decreases upon cell cycle exit induced by TGF-beta or serum starvation (By similarity).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ3TLR7
MaxQBiQ3TLR7
PaxDbiQ3TLR7
PeptideAtlasiQ3TLR7
PRIDEiQ3TLR7

PTM databases

iPTMnetiQ3TLR7
PhosphoSitePlusiQ3TLR7

Expressioni

Gene expression databases

BgeeiENSMUSG00000037474
CleanExiMM_DTL
ExpressionAtlasiQ3TLR7 baseline and differential
GenevisibleiQ3TLR7 MM

Interactioni

Subunit structurei

Component of the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)), at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1. Interacts with CDKN1A and CDT1. Interacts with FBXO11; SCF(FBXWO11) controls DTL stability but DCX(DTL) does not control FBXO11 stability (By similarity).By similarity

Protein-protein interaction databases

BioGridi21834532 interactors.
IntActiQ3TLR7 31 interactors.
STRINGi10090.ENSMUSP00000027933

Structurei

3D structure databases

ProteinModelPortaliQ3TLR7
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati47 – 89WD 1Add BLAST43
Repeati96 – 135WD 2Add BLAST40
Repeati138 – 178WD 3Add BLAST41
Repeati214 – 253WD 4Add BLAST40
Repeati269 – 308WD 5Add BLAST40
Repeati313 – 354WD 6Add BLAST42
Repeati358 – 398WD 7Add BLAST41

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi168 – 171DDB1-binding motifBy similarity4
Motifi197 – 203Nuclear localization signalSequence analysis7
Motifi243 – 246DDB1-binding motifBy similarity4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi424 – 546Ser-richAdd BLAST123

Sequence similaritiesi

Belongs to the WD repeat cdt2 family.Curated

Keywords - Domaini

Repeat, WD repeat

Phylogenomic databases

eggNOGiKOG0321 Eukaryota
ENOG410XRWK LUCA
GeneTreeiENSGT00530000064210
HOVERGENiHBG057737
InParanoidiQ3TLR7
KOiK11790
OMAiQISGAHN
OrthoDBiEOG091G04RK
PhylomeDBiQ3TLR7
TreeFamiTF324483

Family and domain databases

Gene3Di2.130.10.102 hits
InterProiView protein in InterPro
IPR015943 WD40/YVTN_repeat-like_dom_sf
IPR001680 WD40_repeat
IPR019775 WD40_repeat_CS
IPR017986 WD40_repeat_dom
IPR036322 WD40_repeat_dom_sf
PfamiView protein in Pfam
PF00400 WD40, 5 hits
SMARTiView protein in SMART
SM00320 WD40, 5 hits
SUPFAMiSSF50978 SSF50978, 2 hits
PROSITEiView protein in PROSITE
PS00678 WD_REPEATS_1, 2 hits
PS50082 WD_REPEATS_2, 5 hits
PS50294 WD_REPEATS_REGION, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q3TLR7-1) [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
MLFNSVLRQP QLGVLRNGWS SHYPLQSLLS GYQCNCNDEH TSYGETGVPV
60 70 80 90 100
PPFGCTFCTA PSMEHILAVA NEEGFVRLYN TESQTSKKTC FKEWMAHWNA
110 120 130 140 150
VFDLAWVPGE LKLVTAAGDQ TAKFWDVRAG ELMGTCKGHQ CSLKSVAFPK
160 170 180 190 200
FQKAVFSTGG RDGNIMIWDT RCNKKDGFYR QVNQISGAHN TADKQTPSKP
210 220 230 240 250
KKKQNSKGLA PAVDSQQSVT VVLFQDENTL VSAGAVDGII KVWDLRKNYT
260 270 280 290 300
AYRQEPIASK SFLYPGTSTR KLGYSSLVLD STGSTLFANC TDDNIYMFNM
310 320 330 340 350
TGLKTSPVAV FNGHQNSTFY VKSSLSPDDQ FLISGSSDEA AYIWKVSMPW
360 370 380 390 400
HPPTVLLGHS QEVTSVCWCP SDFTKIATCS DDNTLKIWRL NRGLEEKPGD
410 420 430 440 450
KHSIVGWTSQ KKKEVKACPV TVPSSQSTPA KAPRAKSSPS ISSPSSAACT
460 470 480 490 500
PSCAGDLPLP SSTPTFSVKT TPATTRSSVS RRGSISSVSP KPLSSFKMSL
510 520 530 540 550
RNWVTRTPSS SPPVTPPASE TKISSPRKAL IPVSQKSSQA DACSESRNRV
560 570 580 590 600
KRRLDSSCLE SVKQKCVKSC NCVTELDGQA ESLRLDLCCL SGTQEVLSQD
610 620 630 640 650
SEGPTKSSKT EGAGTSISEP PSPVSPYASE GCGPLPLPLR PCGEGSEMVG
660 670 680 690 700
KENSSPENKN WLLAIAAKRK AENSSPRSPS SQTPSSRRQS GKTSPGPVTI
710 720
TPSSMRKICT YFRRKTQDDF CSPEHSTEL
Length:729
Mass (Da):79,131
Last modified:February 6, 2007 - v2
Checksum:iC828FAFBA9929360
GO
Isoform 2 (identifier: Q3TLR7-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     699-729: TITPSSMRKICTYFRRKTQDDFCSPEHSTEL → SLNVGGHMSYLKGTRCSSQDCLGIQANNFALLLH

Note: No experimental confirmation available.
Show »
Length:732
Mass (Da):79,101
Checksum:iE64F9ACAE69103B4
GO
Isoform 3 (identifier: Q3TLR7-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     214-216: DSQ → VR
     217-729: Missing.

Note: No experimental confirmation available.
Show »
Length:215
Mass (Da):23,883
Checksum:i4DBF06F1375457F8
GO

Sequence cautioni

The sequence BAE36376 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BC060208 differs from that shown. Reason: Frameshift at position 163.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti110E → G in BAE36376 (PubMed:16141072).Curated1
Sequence conflicti149P → S in BAE38725 (PubMed:16141072).Curated1
Sequence conflicti200P → L in BAB28549 (PubMed:16141072).Curated1
Sequence conflicti300M → T in BAC76405 (PubMed:12707369).Curated1
Sequence conflicti300M → T in BAC76404 (PubMed:12707369).Curated1
Sequence conflicti369C → Y in BAC76405 (PubMed:12707369).Curated1
Sequence conflicti369C → Y in BAC76404 (PubMed:12707369).Curated1
Sequence conflicti593T → A in BAE38725 (PubMed:16141072).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_022884214 – 216DSQ → VR in isoform 3. 1 Publication3
Alternative sequenceiVSP_022885217 – 729Missing in isoform 3. 1 PublicationAdd BLAST513
Alternative sequenceiVSP_022886699 – 729TITPS…HSTEL → SLNVGGHMSYLKGTRCSSQD CLGIQANNFALLLH in isoform 2. 1 PublicationAdd BLAST31

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB095735 mRNA Translation: BAC76404.1
AB095736 mRNA Translation: BAC76405.1
AK012919 mRNA Translation: BAB28549.1
AK054412 mRNA Translation: BAC35769.1
AK133177 mRNA Translation: BAE21543.1
AK161401 mRNA Translation: BAE36376.1 Different initiation.
AK166351 mRNA Translation: BAE38725.1
BC060208 mRNA No translation available.
CCDSiCCDS15621.1 [Q3TLR7-1]
RefSeqiNP_001292162.1, NM_001305233.1
NP_084042.1, NM_029766.3 [Q3TLR7-1]
UniGeneiMm.189102

Genome annotation databases

EnsembliENSMUST00000027933; ENSMUSP00000027933; ENSMUSG00000037474 [Q3TLR7-1]
GeneIDi76843
KEGGimmu:76843
UCSCiuc007eck.2 mouse [Q3TLR7-1]
uc007ecn.2 mouse [Q3TLR7-4]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiDTL_MOUSE
AccessioniPrimary (citable) accession number: Q3TLR7
Secondary accession number(s): Q3TTE9
, Q6PAN1, Q80WY1, Q80WY2, Q8BW38, Q9CZ76
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 6, 2007
Last sequence update: February 6, 2007
Last modified: February 28, 2018
This is version 117 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome